Experiments have been performed to document the in vitro binding of cocaine, benzoylecgonine (BE), amphetamine, and N-acetylamphetamine (N-AcAp) to synthetic melanin subtypes. The two predominant melanin types in hair are the black eumelanins and the reddish-brown pheomelanins. The melanins included in this study are two black eumelanin subtypes [5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derived melanins], a reddish-brown pheomelanin [from 5-cysteinyl-S-Dopa (5-CysDOPA)], and two mixed eu-/pheomelanin copolymers. Results indicate that the basic drugs cocaine and amphetamine bind to eumelanins and mixed eu-/pheomelanins to varying degrees, but not to pure pheomelanin. BE and N-AcAp, net neutral molecules, do not bind to any type of melanin. As a model of which eumelanin chemical functional groups bind drugs, amphetamine was shown, using tandem mass spectrometry, to form a noncovalent adduct with dimerized oxidized catechol. Similar functional groups on the eumelanin polymer may represent an important drug-binding site. Overall, these findings show that basic drugs have a greater affinity for melanin than their net neutral analogues, reveal that melanin types differ when it comes to drug binding, help elucidate what properties of melanin are important for drug binding, and help explain why hair color biases exist.