The increased incidence of malignant melanoma in the last decades, its high mortality and pronounced therapy resistance pose an enormous challenge. Important therapeutic targets for melanoma are the induction of apoptosis and suppression of survival pathways. Preclinical studies have demonstrated the efficacy of pro-apoptotic Bcl-2 proteins and of death receptor ligands to trigger apoptosis in melanoma cells. In the clinical setting, BH3 domain mimics and death receptor agonists are therefore considered as promising, specific novel treatments to add to the conventional pro-apoptotic strategies such as chemo- or radiotherapy. However, constitutively activated survival pathways, in particular the mitogen-activated protein kinases, protein kinase B/Akt and nuclear factor (NF)-kappaB, all may work in concert to prevent effective therapy. Thus, selective biologicals developed with the aim to inhibit pro-survival signaling are currently tested in melanoma. For highly therapy-resistant tumors such as melanoma, development of novel drug combinations will be essential, and combinations of survival inhibitors and pro-apoptotic mediators appear most promising. The challenge of the near future will be to make a rational choice of the multiple possible combinations and protocols. This review gives a critical overview of proteins involved in melanoma chemoresistance, which are targets for current drug development leading to the best choice for future trials.