Bcl-2 family proteins play a pivotal role in regulating programmed cell death that is essential for cell homeostasis in multicellular organisms. Tumors develop when cells bypass regulated cell death and grow faster than they die, while in degenerative diseases there is too much cell death. Thus understanding how Bcl-2 proteins modulate cell survival will provide novel important insight into therapeutic targets, as evidenced by recent successes specifically targeting and killing cancer cells. Here we describe the current models for regulation of apoptosis by Bcl-2 family proteins with a specific emphasis on the predicted therapeutic targets. Limited success of current efforts in targeting Bcl-2 family proteins including antisense oligonucleotides and small-molecule inhibitors suggests that emerging techniques and strategies will be required to identify a new generation of drugs targeting Bcl-2 family proteins. We review some of the more promising therapeutic opportunities for treating diseases that have been revealed by our current mechanistic understanding of these proteins.