The Las Plagas (The Plagues) are a breed of ancient parasites hailing from a remote section of Spain, which died when the first castellan of the area had them sealed to prevent their resurgence, after being originally controlled by a cult calling themselves "Los Illuminados", the enlightened, in Spanish. These parasites could latch into a victim's spine and, if the victim complied, it could control these people, making them puppets to the parasite's will; these people were called Ganados, "cattle", or in a rarer acceptation, "earned" or "won" in Spanish. A cultist preacher, Osmund Saddler, learnt of the parasites' existence and convinced the current castellan, Ramón Salazar, of destroying the seals and allowing the Plaga to roam again unchecked. This set in motion the events of Resident Evil 4.

The neighboring communities adjacent to Salazar's domain were injected with the resurrected parasites, and soon some Plaga ran rampant and the Illuminados cult was resurrected. Saddler then employed a scientist, Luis Sera, to improve upon the parasites' abilities, to control hosts, to enhance strength, and other applications. Sera was favored for the job as he had a grandfather in the region. However, soon other scientists became involved in Plaga research, and it became apparent the Plagas were being developed for bio-weapons development. Eventually Sera realized his research had been used to toughen the Plaga against removal, and sought to escape. However, he was unsuccessful. Under the orders of Saddler, who wielded the Master Plaga sample, the group, the new Illuminados cult machinated the kidnapping of the daughter of the United States President, Ashley Graham, took her to the Los Illuminados region, and had her injected with a slave Plaga egg.

Agent Leon S. Kennedy, of the Presidential Guard, was sent in to seek out Ashley, but was eventually injected with a slave Plaga himself. After struggling with the Plaga development for as long as he could while battling countless Plaga freaks, with special medication provided by Luis, he eventually reached a Plaga removal device and destroyed the parasites within him and Ashley. He then battled Saddler, in a monstrous shape, and destroyed him; this destroyed as well all slave Plagas under Saddler's control. However, a Master Plaga sample, stolen by Luis and dropped by Saddler upon death, was stolen from Leon himself by Ada Wong, who delivered it to her superiors and handed a fake sample to Wesker. Unfortunately for Ada's bosses, Wesker was not fooled at all and soon enough he had his own Plaga samples to manipulate.

Later, upon the encroaching shadows of Resident Evil 5, Wesker made his move and unleashed upon the Kijuju region of Africa evolved Plaga samples, mutated by interaction with the T-Virus. Type-2 Plagas were then used to create Majini, "evil spirits" in Swahili. These parasites were born ready for infection, and forcefully jammed down the victims' throats and turned them into mindless puppets in seconds, rather than the original Plaga, which needed days and the compliance of the host to attain full control. Also, Type-3 Plagas were inoculated into the workers of a nearby oil field, and though not as easily transmissible and could not be extended to women or children were able to top the Type-2 Plaga performance in almost every field. All Plagas of these kinds were killed by the end of Resident Evil 5.

The standard Plagas were able to parasitize many walks of life, though they were not as versatile as the T-Virus with beings such as vermin and bugs, as the parasites required a certain size to attain control and needed direct contact with the host's spine. Other unconventional Plaga caused some mutations in humans, creating abominations such as the Novistador monsters, the Verdugo or insane creations such as the genetically engineered beings Wesker created with his own Plaga samples.