(Fortune Magazine) -- Years before Melinda French met and married Bill Gates, she had a love affair - with an Apple computer. � She was growing up in Dallas in a hard-working middle-class family. Ray French, Melinda's dad, stretched their budget to pay for all four children to go to college. An engineer, he started a family business on the side, operating rental properties. "That meant scrubbing floors and cleaning ovens and mowing the lawns," Melinda recalls. The whole family pitched in every weekend. When Ray brought home an Apple III computer one day when she was 16, she was captivated. "We would help him run the business and keep the books," she says. "We saw money coming in and money going out."

Of all the tricks that life can play, it's hard to imagine any stranger than what befell Melinda French. Today she is living in a gargantuan high-tech mansion on the shores of Lake Washington, married to the richest man in America - and giving billions of dollars away. When she married Bill Gates 14 years ago, she bought into a complex bargain. On the one hand, she became half of what has turned out to be the world's premier philanthropic partnership. The Bill & Melinda Gates Foundation has assets of $37.6 billion, making it the world's largest. In that total is $3.4 billion that Warren Buffett has already given, and still to come are nine million Berkshire Hathaway B shares, currently worth $41 billion, that he has pledged to contribute in coming years. Assuming that Berkshire (BRKA, Fortune 500) shares continue to rise and that the Gateses continue to bestow their own wealth on their foundation, Melinda and Bill will very likely give away more than $100 billion in their lifetimes. Already the foundation has disbursed $14.4 billion - more than the Rockefeller Foundation has distributed since its creation in 1913 (even adjusted for inflation).

Along the way, Melinda has sacrificed privacy, security, simplicity, and normalcy. In the late 1990s, during the Microsoft antitrust trial, her husband was widely regarded as the biggest bully in business. And isn't anyone married to Bill Gates susceptible to losing her identity - to being perceived as the ultimate accessory?

Forgive her if she overcompensates. One day this past fall she spent many hours at her children's school (the Gateses have two daughters, ages 5 and 11, and a son, 8) and then hosted a dozen dinner guests, including four African health ministers who were in Seattle for the Bill & Melinda Gates Foundation Malaria Forum. By 10 P.M., after everyone had left, she was feeling frazzled and panicky about her speech the next morning. "Just go to bed!" Bill told her. "You know so much about malaria." Melinda dreads the spotlight, but the following morning she faced more than 300 scientists, doctors, and health officials. She unveiled an audacious plan to eradicate malaria - a disease that kills more than one million people annually and has eluded a cure for centuries - and then answered questions with Bill. Afterward the crowd buzzed about this woman whom even they, recipients of the Gateses' billions, hardly know.

Today, at 43, Melinda Gates is ready to reveal her full self - to go public, so to speak. "I had always thought that when my youngest child started full-day school I'd step up," she says, sitting down with Fortune for her first-ever profile. Although she admits she would prefer to stay out of public view forever, her older daughter got her thinking. "I really want her to have a voice, whatever she chooses to do," she says. "I need to role-model that for her." She is spending more time on foundation work, up to 30 hours a week. "As I thought about strong women of history, I realized that they stepped out in some way."

She is stepping up also because her husband is doing the same. Beginning in July, Bill, who is nine years older than Melinda, plans to spend more than 40 hours a week on philanthropy, leaving 15 or so for his duties as chairman of Microsoft. Friends of the couple say that he wouldn't be shifting gears if it weren't for Melinda. Moreover, they say, she has helped Bill become more open, patient, and compassionate. "Bullshit!" he bellows. Nicer, perhaps? "No way!" he shouts, grinning because he knows it's true. One thing he admits readily: Thanks to Melinda, he is easing comfortably into his new role. About the philanthropic work he says, "I don't think it would be fun to do on my own, and I don't think I'd do as much of it."

This is not exactly a marriage of equals. Melinda is better educated than Bill, having graduated from Duke University with a BA (a double major in computer science and economics) and an MBA. Harvard's most celebrated dropout, Bill was awarded an honorary degree last June. Melinda also outperforms him athletically. She runs once a week with a few friends - seven miles in an hour, a brisk pace - and tries to exercise five days a week. She has completed the Seattle marathon and climbed, with ropes and crampons, to the peak of 14,410-foot Mount Rainier. As for Bill, Melinda says, "He's finally started to run in the last year." To give him credit, he is an aggressive tennis player and a decent golfer - sometimes playing with Melinda. Beyond that, though, running on the treadmill while watching DVDs three nights a week is all Bill can do to keep up with his fit wife.

Melinda also understands people better than he does, Bill admits. In fact, he uses her as a sounding board, sometimes for personnel matters at Microsoft (MSFT, Fortune 500). In 2000, when Steve Ballmer, with whom Bill has worked for 28 years, replaced him as CEO, Melinda helped ease the awkward transition. "Melinda and I would brainstorm about it," Bill says. "You always benefit from your key confidante telling you, 'You think so-and-so stepped on your toes? Well, maybe he didn't mean to. Maybe you're wrong.'" Says the couple's close friend Warren Buffett, who has known them since 1991: "Bill really needs her."

When it comes to investing their philanthropic assets, Melinda wields even greater influence. Early on she and Bill agreed to focus on a few areas of giving, choosing where to place their money by asking two questions: Which problems affect the most people? And which have been neglected in the past? While many philanthropists take the same tack, the Gateses, who love puzzles, apply particular rigor. "We literally go down the chart of the greatest inequities and give where we can effect the greatest change," Melinda says. So while they don't give to the American Cancer Society, they have pumped billions into the world's deadliest diseases - most importantly AIDS, malaria, and tuberculosis - and failing public high schools in the U.S. And while Bill is drawn, naturally, to vaccine research and scientific solutions that may be decades away, Melinda is interested in alleviating suffering right now. "You can't save kids just with vaccines," she says. "I'd go into rural villages in India and think, 'Okay, we saved this child. But the cows are defecating in the stream coming into the village. There are other things we need to be doing.'"

Those other things include funding insecticide-treated bed nets to ward off malaria-carrying mosquitoes, providing microbicides to prevent the transmission of AIDS, and offering microloans and insurance to help the poorest of the poor start businesses and farms. The Gateses' latest mission, which developed out of a trip Melinda took to Kenya two years ago, is to recreate for Africa a green revolution similar to the program that increased crop yields in Latin America and Asia beginning in the 1940s. In 2006 the Gates Foundation formed a $150 million alliance with the Rockefeller Foundation. "Melinda is a total-systems thinker," says Rockefeller president Judith Rodin. "She and Bill dive into issues. They care deeply, deeply, deeply about making a difference, but they don't get starry-eyed. They demand impact."

The impact comes from the combination of Melinda's holistic vision and Bill's brainpower. Bono, the rock star-humanitarian who is both a friend of the Gateses and a grantee (through his One antipoverty campaign), calls their relationship "symbiotic." Noting Bill's fierceness, Bono says, "Sometimes I call him Kill Bill. Lots of people like him - and I include myself - are enraged, and we sweep ourselves into a fury at the wanton loss of lives. What we need is a much slower pulse to help us be rational. Melinda is that pulse." Buffett also believes that Melinda makes Bill a better decision-maker. "He's smart as hell, obviously," Buffett says. "But in terms of seeing the whole picture, she's smarter." Would Buffett have given the Gates Foundation his fortune if Melinda were not in the picture? "That's a great question," he replies. "And the answer is, I'm not sure."