Genotoxic damage, as induced by cisplatin, has been reported to lead to upregulation of pro-apoptotic members of the Bcl-2 family. We have here examined the pro-apoptotic Bcl-2 proteins Bak and Bax in human melanoma cells treated with cisplatin. Expression of Bak was not increased by this treatment; instead, equitoxic doses of cisplatin were found to induce the pro-apoptotic conformation of Bak in all human melanoma cell lines tested, irrespective of p53 status. Unlike Bak modulation, cisplatin-mediated modulation of Bax was seen in only one of the p53 wildtype cell lines. The upstream regulation of Bak is not known. We show that expression of a kinase-inactive fragment of the stress-activated kinase MEKK1 (dnMEKK) blocks modulation of Bak and apoptosis. Activation of the downstream kinases JNK1-2, which regulate activity of transcription factor c-Jun, has been shown to be involved in cisplatin-induced apoptosis. Although dnMEKK inhibited apoptosis, JNK1-2 activation was not blocked. Conversely, expression of a kinase-active MEKK1 fragment (dpMEKK) was able to modulate Bak and to induce apoptosis in a cell-line-dependent manner. We conclude that a pro-apoptotic MEKK1 pathway is necessary for cisplatin-induced Bak modulation, and that this modulation represents one of several cisplatin-induced apoptotic mechanisms/processes.