Over the last few years, evidence has accumulated showing that cell cycle regulation of T cells is essential to establish tolerance and to suppress autoimmunity. Although apoptosis has been considered an important mechanism in the control of tolerance and autoimmunity development, cell cycle regulation also constitutes a pivotal alternative pathway in the prevention of autoreactivity. Several cell cycle-associated molecules act as autoimmunity suppressors. The cell cycle inhibitors p21 and p27 have recently been shown to control T cell tolerance, while p21 also restrains development of autoimmunity. In this review, we will explore the effects of p21 and p27 in T cell tolerance induction and discuss the association between tolerance loss and autoimmunity development in p21-/- mice.