Cisplatin induces the pro-apoptotic conformation of the Bcl-2 family protein Bak in four out of four human melanoma cell lines, whereas an effect on the pro-apoptotic conformation of Bax was seen in only one (FM55 cells). Expression of a kinase-inactive fragment of MEKK1 (dnMEKK) efficiently blocked the modulation of Bak and cytochrome c release, whereas DEVDase activation and nuclear fragmentation were reduced by half. Expression of a kinase-active MEKK1 fragment (dpMEKK) was sufficient to modulate Bak in three out of four cell lines, whereas an effect on Bax was seen only in FM55 cells. In the DFW cell line, dpMEKK stimulated a similar degree of Bak modulation as cisplatin but did not induce nuclear fragmentation. Together with the knowledge that dnMEKK was insufficient to block apoptosis completely, this finding indicates that cisplatin may induce apoptosis by means of additional mechanisms. 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 or processes.