Activation of the phosphoinositide 3-kinase (PI3K) pathway promotes proliferation and survival in many different cell types of the immune system. PI3K acts downstream of receptors that mediate proliferation and survival in T cells, and required roles for individual class I PI3K catalytic isoforms have been established. Interestingly, mice with either augmented or diminished PI3K activity in T cells develop lymphoproliferation and signs of autoimmunity. Here, we summarize our current knowledge of mouse strains with hyperactive or reduced PI3K, different isoforms of class I PI3K in T cell-mediated immunity and autoimmunity, and the therapeutic implications for modulating this pathway for treatment of various autoimmune diseases.