Although mutations of the retinoblastoma gene (RB1) contribute to malignant progression in many types of tumor, the role of RB1 mutation in cancer initiation is highly restricted to the rare embryonic tumor, retinoblastoma. However, RB1 is expressed and its product, p110RB1, is regulated through the cell cycle in many tissues. This apparent paradox may be clarified by the emerging evidence that p110RB1 functions as a regulator of transcription of cell cycle genes. Tissue specific effects may be determined by the cellular proteins that interact with p110RB1, or by cell type-specific expression of target genes regulated by p110RB1.