By deciphering the dysregulation of apoptosis in melanoma cells, new treatment approaches exploiting aberrant control mechanisms regulating cell death can be envisioned. Among the Bcl-2 family, a BH3-only member, NOXA, functions in a specific mitochondrial-based cell death pathway when melanoma cells are exposed to a proteasome inhibitor (e.g., bortezomib). Some therapeutic agents, such as bortezomib, not only induce proapoptotic Bcl-2 family members and active conformational changes in Bak and Bax but also are associated with undesirable effects, including accumulation of antiapoptotic proteins, such as Mcl-1. To enhance the bortezomib-mediated killing of melanoma cells, the apoptotic pathway involving NOXA was further investigated, leading to identification of an important target (i.e., the labile Bcl-2 homologue Mcl-1 but not other survival proteins). To reduce Mcl-1 levels, melanoma cells were pretreated with several different agents, including Mcl-1 small interfering RNA (siRNA), UV light, or the purine nucleoside analogue fludarabine. By simultaneously triggering production of NOXA (using bortezomib) as well as reducing Mcl-1 levels (using siRNA, UV light, or fludarabine), significantly enhanced killing of melanoma cells was achieved. These results show binding interactions between distinct Bcl-2 family members, such as NOXA and Mcl-1, in melanoma cells, paving the way for novel and rational therapeutic combination strategies, which target guardians of the proapoptotic Bak- and Bax-mediated pathways, against this highly aggressive and often fatal malignancy.