The promyeloctyic leukemia protein (PML) has established activities as a potent repressor of proliferation, and oncogenic transformation, a promoter of apoptosis, an inducer of senescence, and may act as an inhibitor of angiogenesis in mammalian systems. Loss of PML or its nuclear bodies is associated with many human disease states. At the molecular level, the PML protein, and its associated nuclear bodies, play roles in diverse events ranging from mRNA export to DNA repair. PML expression impacts on Akt survival signaling, p53/Mdm2 activity, and cell cycle progression, to name a few. However, there is no discrete set of molecular activities associated with the PML protein that underlie its biochemical and physiological effects. In this review, we postulate a possible molecular model of PML function that could provide a unifying underpinning for many of its disparate activities. In particular, we explore how the ability of PML to coordinately and combinatorially regulate gene expression post-transcriptionally, enables PML to have such broad ranging effects on cellular physiology.