Melanin plays a key role in our skin, protecting us against ultraviolet radiation, but there are situations in which its anomalous accumulation can lead to either aesthetic problems or diseases like melasma. For this reason, it is important to find agents that are able to decrease the skin pigmentation. It has been demonstrated that the melanin synthesis pathway can be inhibited at different levels by different mechanisms of action. The aim of this project is to combine some of these agents with different mechanisms of action on this pathway in order to find synergistic effects in the inhibition of tyrosinase and melanin synthesis. Kojic acid + α-lipoic acid combination are the only ones that have shown a synergistic effect over mushroom tyrosinase. However, this effect is not seen in melanin synthesis inhibition, although this combination is the most effective one. A potentiation effect is seen in arbutin + α-lipoic acid and kojic acid + azelaic acid combination. Kojic acid and α-lipoic acid combination might prove a good approach as treatment for hyperpigmentation disorders.