Unevenness of skin tone is a pervasive problem that develops with aging and sun exposure. Skin color results from the action of multiple biologic pathways that primarily control melanin synthesis and distribution. In the present studies we explored the possibility of using a synergistic approach to enhance the efficacy of cosmetic products. We evaluated the in vitro and clinical efficacy of a combination of 4-hexyl resorcinol, a known tyrosinase inhibitor and niacinamide, a melanosome transfer inhibitor, both of which regulate two different process involved in the development of skin color. Our in vitro studies using human recombinant tyrosinase enzyme showed that 4-hexyl resorcinol is one of the most potent tyrosinase inhibitors and it inhibits the diphenolase activity of tyrosinase enzyme. The combination of 4-hexyl resorcinol and niacinamide show synergistic reduction in melanin production in cultured melanocytes as well as in a 3D Episkin model as measured by a spectrophotometer. A half-face, double-blind, randomized clinical study was conducted on Chinese volunteers to evaluate the efficacy of 4-hexyl resorcinol in combination with niacinamide against niacinamide alone in a cosmetic formulation. Volunteers applied formulations twice a day for 12 weeks and the effect on various skin parameters were assessed at baseline and weeks 1, 4, 8, and 12. We found that, though both formulations showed significant efficacy from baseline 4-hexyl resorcinol and niacinamide combination outperformed niacinamide alone on both visual and instrumental attributes of aging, hyperpigmentation, and firmness. These studies demonstrate that a product designed to affect multiple pathways of melanogenesis and melanin distribution provide an effective route to improving the appearance of hyperpigmentation.