Melanin is both photosensitizer and photoprotector. Skin cancer rates decrease with increasing constitutive pigmentation, yet the pigment has been shown to be photoreactive and capable of producing damaging reactive oxygen species. We utilized model systems of related cells or similar cell type that vary in constitutive and in induced pigment. Induction of eumelanin in Cloudman S91 mouse melanoma cells leads to less UV-induced killing and to less mutation induction at the ouabain locus (Na+, K(+)-ATPase). Pigmented mouse melanocytes, melan-b (brown) and melan-a (black) were slightly less sensitive than melan-c (albino) melanocytes to killing after UVC and UVA but were more sensitive to killing after UVB and UVB + UVA. Pigment had a small sensitizing effect on pyrimidine dimer DNA damage in both the melanoma cells and the melanocytes. The lack of consistency in these results suggests that intracellular pigment may disregulate the milieu intérieur resulting in end effects that are unrelated to the original genomic damage.