Skin cancer has reached epidemic proportions and is considered to be a direct consequence of ultraviolet (UV) radiation exposure. Excessive exposure of epidermal cells to UV results in apoptosis of irreparably damaged cells to avoid malignant transformation. The Bcl-2 family of proteins is emerging as a crucial regulator of epidermal homeostasis and cell's fate in the stressed skin. Not surprisingly, deregulation of Bcl-2 family members is also chiefly involved in skin carcinogenesis and response to cancer therapy. Here we discuss the physiopathological role of epidermal Bcl-2 family members, their implications in skin carcinogenesis and as potential targets in cancer therapy.