Apart from their coordinated inactivation by DNA tumor viral oncoproteins, the pRB and p53 tumor suppressor pathways were not known to be connected ten years ago. Within the last decade, our appreciation of how these pathways are interconnected has grown substantially. The checks and balances that exist between pRB and p53 involve the regulation of the G1/S transition and its checkpoints, and much of this is under the control of the E2F transcription factor family. Following DNA damage, the p53-dependent induction of p21CIP1 regulates cyclin E/Cdk2 and cyclin A/Cdk2 complexes both of which phosphorylate pRB, leading to E2F-mediated activation. Similarly, E2F1-dependent induction of p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53 stabilization and potentially p53-mediated apoptosis or cell cycle arrest. From the existing mouse models discussed above, we also know that proliferation, cell death and differentiation of distinct tissues are also intimately linked through entrance and exit from the cell cycle, and thus through pRB and p53 pathways. Virtually all human tumors deregulate either the pRB or p53 pathway, and often times both pathways simultaneously, which is critical for crippling cellular defense against neoplasia. The next decade of cancer research will likely see these two tumor suppressor pathways only merge even more.