The promyelocytic leukemia protein (PML) is a tumor suppressor identified in acute PML and implicated in the pathogenesis of a variety of tumors. PML is essential for the proper assembly of a nuclear macromolecular structure called the PML nuclear body (PML-NB). PML and PML-NBs are functionally promiscuous and have been associated with the regulation of several cellular functions. Above all these is the control of apoptosis, a function of PML whose physiological relevance is emphasized by in vivo studies that demonstrate that mice and cells lacking Pml are resistant to a vast variety of apoptotic stimuli. The function of PML in regulating apoptosis is not confined to a linear pathway; rather, PML works within a regulatory network that finely tunes various apoptotic pathways, depending on the cellular context and the apoptotic stimulus. Here, we will summarize earlier and recent advances on the molecular mechanisms by which PML regulates apoptosis and the implication of these findings for cancer pathogenesis.