Three negative regulators of cell cycle, the related proteins, pRB, p107 and p130, constitute the family of pocket proteins. pRB is a tumor suppressor which has drawn a lot of attention on its family of proteins, with the ensuing intense study of their biology. As a result we have a wealth of information on their biochemistry and biology, ranging from their regulation to their biochemical activities, and the effects of their absence or overexpression on cells. Despite this, many questions remain unsolved. In recent years, analysis of genetically-modified mouse strains has provided interesting data regarding the physiological and pathophysiological roles of these three proteins. Specifically, germ-line and conditional knockout strains for one or more than one of the members of the family have revealed as powerful tools in this regard. Here we review the mouse models available for studying these cell cycle regulators and how data generated by these approaches have sometimes challenged previous thoughts about the pocket proteins biology.