Low p27 expression in many human cancers is a prognostic indicator for poor outcome. While analysing the mechanism by which p27 deficiency contributed to tumor development in the Rb+/− mouse model, we identified a role for p27 as a proapoptotic tumor suppressor. We examined the cell cycle and apoptotic response of these pituitary tumor cells to the dopamine analog bromocriptine as well as the expression of Arf and other cell cycle and apoptotic regulators in these tumors. We also examined the expression of Arf and its function in mouse embryo fibroblasts either singly or doubly deficient for Rb and p27. From these studies, we concluded that the absence of p27 disabled the trigger for an Arf-dependent apoptotic response in Rb−/− tumor cells. This suggests a novel mechanism by which the loss of p27 may impact on tumor development.