Apoptosis induced by p53 is firmly established as a central mechanism of tumour suppression. In addition to its complex functions as a nuclear transcription factor, p53 can act in the cytosol and mitochondria to promote apoptosis through transcription-independent mechanisms. Recent studies have shown that physical and functional interactions of p53 with various members of the Bcl-2 family provide the basis for this alternative route of p53-mediated cell death. However, different models of how these interactions promote apoptosis have been proposed. This review focuses on the mechanisms, regulation and physiological roles of transcription-independent p53 activities and highlights recent findings suggesting that the utilisation of these activities provides a promising alternative strategy for p53-based cancer therapy.