The adaptive immune system protects its host from a myriad of pathogens. This ability stems from a vast set of lymphocytes, each with a different antigen receptor, a small number of which will bind to antigens derived from a given pathogen. Although the cells within any antigen-specific population appear to be relatively homogenous before antigenic encounter, recent work on T cells indicates that individual cells within the population differentiate in very different ways after exposure to the antigen. We focus here on studies of CD4⁺ T cells and review evidence indicating that variable differentiation of effector cells from single naïve cells is caused by both cell-extrinsic stochastic factors and cell-intrinsic factors related to T cell antigen receptor (TCR) signal quantity and quality.