Thymic T cell differentiation to peripheral T cells aims to assist the generation of effector cells mediating adaptive immune responses. During this process, which takes place during embryogenesis and in adulthood, proliferation is coupled with changes in chromatin organization and transcription. Moreover, B and T lymphocytes start to proliferate and rapidly expand their numbers when activated following an encounter with an antigen. This expansion phase is accompanied by differentiation of naïve T cells and is followed by a period of population contraction, resulting in only a small fraction of the expanded population surviving and entering the memory cell pool. The kinetics of the expansion and contraction affect the speed of antigen clearance and the clinical course of disease. Molecules that are involved in the coordination of proliferation, chromatin reorganization, and transcriptional regulation are likely to play an important role in T cell generation, homeostasis, and disease. Here we review how cell cycle regulators affect lymphoid system development and homeostasis and discuss recent evidence implicating the cell cycle inhibitor Geminin in this process. Geminin has been shown to coordinate proliferation and differentiation by regulating cell cycle progression, chromatin organization, and transcription in the nervous system. In the immune system, progenitor T cell commitment and differentiation progresses normally in the absence of Geminin. However, Geminin is required for TCR response in vitro and T cell proliferation upon lymphopenia-induced proliferation, suggesting that Geminin might be an essential factor for T cell expansion during the immune response.