Knowledge of the emerging pathways of cell death downstream of the p53 tumor suppressor and the TRAIL death-inducing ligand is suggesting ways to improve therapeutic design in cancer. In contrast to its unique G1 cell cycle arresting mechanism that is maintained by p21(WAF1), there are signals transduced by p53 to multiple apoptotic effectors perhaps due to the importance of apoptosis in suppressing tumors. There is evidence for cytoplasmic as well as mitochondrial activation of caspases downstream of p53, although in some cell lineages the signal ultimately involves the mitochondria. The TRAIL signaling pathway appears promising for therapeutic development despite sharing some similarities with the toxic Fas and TNF pathways, in terms of effector molecules and downstream signals. One of the key findings is the tissue specificity of cell death responses, a feature that could be exploited in strategies to widen the therapeutic window of combination cancer therapies. Efforts continue to develop p53-targeted cancer therapy, and novel clues to enhance or block specific effectors may improve therapeutic design.