The induction of variants of L5178Y mouse-lymphoma cells resistant to 1-beta-D-arabinofuranosylcytosine (ara-C) has been investigated. The spontaneous mutation frequency was low, around 3 X 10(-8). Resistant variants were induced in a dose-dependent fashion following treatment with ethyl methanesulphonate (EMS), ethidium bromide and 2-acetylaminofluorene, but not with gamma-irradiation. With EMS as mutagen the frequency of ara-C-resistant variants was much lower than that obtained using other selective agents, whereas it was higher with the mutagens acetylaminofluorene and ethidium bromide. Out of 42 resistant clones examined, 38 showed normal sensitivity to thymidine and were destignated as Class 1, the remaining four (Class 2) were usually resistant to thymidine. Cells in Class 1 did not accumulate detectable amounts of ara-C and had negligible deoxycytidine kinase activity. They were about 3000-fold more resistant to the toxic effects of ara-C than were wild-type cells. Cells in Class 2 had a reduced ability to accumulate are-C and had 50% of the deoxycytidine kinase activity of wild-type cells. They were only 20 times more resistant to ara-c than were wild-type cells. The enzymatic defect in these cells is obscure but the phenotypic properties probably result from subtle alterations in the pool of deoxycytidine nucleotides.