Clinical evidence suggests some lack of cross resistance between vincristine (VCR) and vindesine (VDS). To investigate this phenomenon experimentally, drug-resistant L5178Y lymphoblast cell lines have been derived in vitro. These lines, under conditions of continuous drug exposure, exhibit a 50-fold order of resistance. Resistance appears due, at least in part, to impaired cellular drug accumulation and retention. Exposure of these resistant cells to VCR or VDS for 24 h showed that the presence or absence of cross resistance was dose-dependent, being most noticeable at low concentrations (less than 0.5 ng/ml) and absent at higher drug levels. Cross resistance also showed some dose-dependency for vinblastine and formyl-leurosine, but this was not seen with other drugs. Marked and complete cross resistance at all concentrations tested was noted with adriamycin and 4'-epiadriamycin in both resistant lines, which, however, retained the same sensitivities as the parent line to VM26, VP-16-213, 5-fluorouracil, and methotrexate. Responses to actinomycin D and mAMSA differed in these two resistant lines. VDS-resistant cells exhibited cross resistance to both drugs, whilst VCR-resistant cells showed only slight resistance to actinomycin D whilst retaining full sensitivity mAMSA. This observation that cross resistance between VCR and VDS is not invariable in vitro appears to reflect clinical experience.