Experiments with various topically applied compounds have demonstrated that 2-mercaptoethylamine HCI (MEA) and N(2-mercaptoethyl)-dimethylamine HCI (MEDA) are very potent agents that cause depigmentation in treated areas only. When applied to the skin of black guinea pigs, they inhibited melanogenesis, acted selectively on melanocytes, decreased melanocyte density significantly, and rendered the few remaining melanocytes degenerative. In epidermis from MEDA-treated areas, melanocytes could be detected only rarely by electron microscopy. Those that were found contained few melanized melanosomes, many vacuoles, and swollen mitochondria. Depigmentation by any exogenous agent can result from destruction or loss of melanocytes; interference with (1) the biosynthesis of premelanosomes and melanosomes, (2) the conversion of tyrosine to dopa to melanin, (3) the biosynthesis of tyrosinase or the active center of the enzyme, (4) the transfer of melanosomes to keratinocytes; and alteration of the melanin present in melanosomes. Depigmentation by MEDA appears to result from selective destruction or degeneration of melanocytes.