Lymphopenia-induced proliferation (LIP) occurs when resources for T cell survival in a host are in excess. LIP has been associated with the development of inflammatory disease in situations where an additional disease-predisposing cofactor is present during LIP. This has led to the view of LIP-driven autoimmunity as a two hit model; however, not all cofactors have equal ability to precipitate autoimmunity and we have recently shown that in some circumstances, such as the absence of the coinhibitory molecule PD-1, additional hits are required. Herein we review factors controlling LIP, including coinhibitory molecules and other attenuators of TCR signaling, with a focus on their contribution to LIP-driven autoimmunity. Rather than viewing LIP-associated autoimmunity as an n-hit model, we suggest a more quantitative view of lymphopenia with respect to the factors that promote LIP as a tool to predict autoimmune potential and to inform tumor immunotherapy approaches.