The in vitro experiments on the interaction of 3H-cocaine and melanin from Sepia officinalis confirmed the existence of drug binding sites on melanin granules. The results suggested that the binding of 3H-cocaine to melanin could be analyzed by assuming that the binding to the surface of pigment granules is analogous to the adsorption of a drug on a solid and follows Langmuir adsorption isotherm type I. Scatchard analysis indicated heterogeneity of binding sites. Structural and chemical alterations caused by isolation of the melanoproteins, which are heterogeneous in nature and show different physico-chemical properties, are considered to be most crucial. The studies on hair samples confirmed that melanin-drug interaction occur on the surface of melanin granules. These seem to be of minor importance compared to the drug-melanoprotein loading during melanogenesis for the observed influence of pigmentation on the drug content of hair fibers. From the results it was concluded that in vitro studies on melanin provide limited information and even drug-soaked hair must be regarded as inappropriate for the study of melanin-drug-binding in hair.