Melanogenesis has been regarded as a hazard for pigment cells which are endangered by reactive quinones and semiquinones generated by this process. Normally the potentially cytotoxic species are confined to melanosomes by a limiting membrane and thus separated from the rest of the cell. Our electron microscopic investigation has demonstrated the presence of abnormal and incomplete melanosomes in human melanomas from epidermal and mucosal sites, in melanoma metastases, and in B16 mouse melanoma. We conclude that significant leakage of reactive melanin precursors including free radical species may occur from aberrant melanosomes in pigmented tumors. This would be expected to be reflected by fully extended physiological scavenging mechanisms, and by local and distant manifestations of cytotoxicity: Among these manifestations is free radical damage to the liver, detected by a thiobarbituric acid-reactive substances assay, in B16 melanoma-bearing mice. The efflux of toxic species from abnormal melanosomes may explain both the observed frequent occurrence of necrosis in melanomas and the therapeutic efficacy of tyrosinase substrates and may also be one of the factors influencing the extent of melanogenuria.