Cell cycle checkpoint mechanisms in mammalian cells act through inhibition of cyclin/cyclin-dependent kinase complexes, as well as through tumor suppressor gene products belonging to the retinoblastoma (Rb) gene family. Work over the past year has demonstrated that these anti-proliferative mechanisms influence multiple phases of the cell cycle. For example, the p 21(WAF1/CIP1/sdi1) gene product retards S phase progression in a manner that is antagonized by cyclin A, cyclin E, or the phosphatase 2A-binding activity of simian virus 40 small t antigen. These findings lead to the conclusion that cyclin-dependent kinase activity is involved in the regulation of S phase progression in mammalian cells. While activation of this and other anti-proliferative pathways by DNA damage, serum deprivation, etc. has been intensively investigated, there is little information on how such pathways are triggered during the onset of cellular senescence. Experiments in which histone deacetylase inhibitors were shown to accelerate the onset of a senescence-like state point to one possible explanation, namely, that defects in higher order chromatin structures can activate checkpoint mechanisms, thereby leading to irreversible cell cycle exit.