The p38 alpha mitogen-activated protein kinase has been implicated in the cellular response to genotoxic agents. Here we show that another p38 family member is also activated in response to cisplatin exposure in human melanoma cells. We identified this isoform as p38 gamma based on its recognition by specific antibodies and because, in contrast to p38 alpha, its activity was not affected by SB203580. We also found that etoposide caused a much more discrete phosphorylation of both p38 alpha and p38 gamma than either cisplatin or UV treatment. These results indicate that genotoxic stresses activate several p38 isoforms whose implication in the cellular response might depend on the type of DNA damage.