The p53 tumor suppressor gene is likely the most commonly mutated tumor suppressor gene in human cancer. Its functions include modulation of both cell cycle arrest and apoptosis. Animal models and human clinical data suggest that in some settings, p53 may be prognostically significant, reflecting its role as a key regulator of cell death during cancer therapy. Two recent strategies have been proposed to exploit p53's unique death-regulating activity in opposite directions and improve cancer treatment. One approach seeks to inhibit p53 in normal cells thereby diminishing therapy-related, p53-dependent toxicity. The other utilizes a peptide derived from the C-terminus of p53 to activate wild-type or mutant p53 proteins, triggering apoptosis with selectivity for transformed cells. These novel approaches hold promise for targeting p53 in cancer therapy and may shed light on mechanisms underlying the role of p53 in cancer cell survival. Copyright 2000 Harcourt Publishers Ltd.