The retinoblastoma protein pRb is functionally inactivated in most human cancers. Numerous studies in cell culture and animal models suggest that pRb has a unique ability to encourage and enforce permanent cell cycle withdrawal, consistent with its role as a tumor suppressor protein. This cell cycle withdrawal has a generic component involving repression of transcription of genes required for proliferation. In addition, numerous studies hint at additional specific roles for pRb in differentiation of certain tissue types. Further, pRb appears to play a central role in the process of cellular senescence, a tumorsuppressive process characterized by proliferative arrest and phenotypic changes. Both differentiation and senescence pathways influenced by pRb involve direct and indirect interactions with the core machinery involved in cell-type-specific differentiation and cell shape control. This review focuses on pRb's role as an participant in osteoblast differentiation illustrative of a broader role in terminal differentiation. In addition, novel pathways activated by pRb in its role as an inducer of cellular senescence will be discussed.