Homeostasis of cell numbers is achieved by balancing the proliferative and death states of cells. Proper regulation in a cell requires an accurate coordination between these two processes. Indeed, dysregulation of cell cycle progression is essential for the initiation of apoptosis. Retinoblastoma protein (RB) is an important tumor suppressor and a cell cycle regulator. Most recent studies suggest that RB also plays a regulatory role in the process of apoptosis. During the onset of apoptosis, the hyperphosphorylated form of RB (p120/hyper) is converted to a hypophosphorylated form (p115/hypo), which is mediated by a specific protein-serine/ threonine phosphatase activity. Accompanied by the internucleosomal fragmentation of DNA, the newly formed p115/hypo/RB is immediately cleaved by a protease that has properties of the caspase family. During apoptosis, RB is also cleaved in its carboxyl terminus by a caspase-3-like activity. By contrast, the unphosphorylated form of RB (p110/unphos) remains uncleaved during apoptosis. Further studies suggest that p110/unphos/RB functions as an inhibitor of apoptosis. Therefore, regulation of the RB proteolytic activities and consequent RB levels is important for the determination of cellular fate.