The retinoblastoma protein (protein name abbreviated Rb or pRb; gene name abbreviated Rb, RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is inactivated by phosphorylation, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins. Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomavirus, bind and inactivate pRb, this can lead to cancer. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.

In humans, the protein is encoded by the RB1 gene located on chromosome 13—more specifically, 13q14.1-q14.2. If both alleles of this gene are mutated in a retinal cell, the protein is inactivated and the cells grow uncontrollably, resulting in development of retinoblastoma, hence the "RB" in the name 'pRb'. Thus most pRb knock-outs occur in retinal tissue when UV radiation-induced mutation inactivates all healthy copies of the gene, but pRb knock-out has also been documented in certain skin cancers in patients from New Zealand where the amount of UV radiation is significantly higher.

Two forms of retinoblastoma were noticed: a bilateral, familial form and a unilateral, sporadic form. Sufferers of the former were over six times more likely to develop other types of cancer later in life, compared to individuals with sporadic retinoblastoma. This highlighted the fact that mutated pRb could be inherited and lent support for the two-hit hypothesis. This states that only one working allele of a tumour suppressor gene is necessary for its function (the mutated gene is recessive), and so both need to be mutated before the cancer phenotype will appear. In the familial form, a mutated allele is inherited along with a normal allele. In this case, should a cell sustain only one mutation in the other RB gene, all pRb in that cell would be ineffective at inhibiting cell cycle progression, allowing cells to divide uncontrollably and eventually become cancerous. Furthermore, as one allele is already mutated in all other somatic cells, the future incidence of cancers in these individuals is observed with linear kinetics. The working allele need not undergo a mutation per se, as loss of heterozygosity (LOH) is frequently observed in such tumours.

However, in the sporadic form, both alleles would need to sustain a mutation before the cell can become cancerous. This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells. Future cancer incidence in sporadic pRb cases is observed with polynomial kinetics, not exactly quadratic as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.

RB1 orthologs have also been identified in most mammals for which complete genome data are available.

RB/E2F-family proteins repress transcription.

pRb is a multifunctional protein with many binding and phosphorylation sites. Although its common function is seen as binding and repressing E2F targets, pRb is likely a multifunctional protein as it binds to at least 100 other proteins.