The retinoblastoma protein (pRB) is a transcriptional cofactor, and the gene that encodes it is mutated in many human tumours. Lees and colleagues uncovered an unexpected transcription-independent role for mouse pRB, by showing that it potentiates mitochondria-mediated cell death (Genes Dev. 27, 1003–1015; 2013). They found that pRB expression enhanced TNF-α-induced apoptosis in a manner that depends on its localization to the mitochondrial outer membrane. They demonstrated that pRB requires the pro-apoptotic factor Bax for this effect, as pRB-associated apoptosis was ablated in Bax knockout cells. The authors showed that pRB interacts directly with Bax to induce release of cytochrome C from the mitochondria, leading to mitochondrial and ultimately cell demise. They identified the pocket domain of pRB as an essential mediator of this effect, and ruled out the involvement of nuclear pRB by using cells that lack endogenous Rb but express Rb with a mutation in its nuclear localization signal. Finally, using a mouse osteosarcoma cell line lacking both endogenous Rb and p53 proteins, but expressing the pRB pocket domain fused to a mitochondrial localization signal and deleted of the nuclear localization signal, the authors demonstrated that pRB-mediated effects on cell death decrease tumour formation in xenograft assays.