Using Cre-Lox technology to inducibly delete Rb from wild-type, p21- and/or p53-deficient primary hepatocytes, we investigated the role of p53, p21 and pRb in the regulation of liver cell proliferation, polyploidization and death. These cellular decisions are critical to maintaining liver cell replacement in disease, and in determining the likelihood of carcinogenesis in chronic liver injury. Clearly, the present study shows a complex interplay between p53, p21 and pRb, which regulates the likelihood of hepatocytes stimulated from quiescence, to proliferate, undergo polyploidy or die. It reveals that these proteins act both in concert and independently, demonstrating that a small set of key cellular players is common to diverse cell decisions of fundamental importance to disease.