Over the last decade the molecular mechanisms controlling programmed cell death (apoptosis) have become clearer. It appears that many physiological and damage signals activate the cell death machinery by inhibiting the pro-survival Bcl-2 proteins. Since many chemotherapeutic drugs used to treat cancers activate the cell death machinery indirectly, there is much interest in developing peptide and non-peptide mimics of the BH3-only proteins, a family of proteins that act as direct antagonists of Bcl-2, as novel anti-cancer agents. This commentary review current progress in our search for such drugs and discusses recent findings in light of our current understanding of the cell death signaling. The potential for discovering novel agents that may form a useful part of the treatment of malignant disease is enormous but we still lack critical understanding of precisely how Bcl-2 function. However, the frequency of mutations affecting proteins that (directly or indirectly) impinge on apoptosis suggests that the approach of targeting Bcl-2 might be a profitable one.