T cell help for antibody production is a fundamental aspect of immune responses. Only recently has a better understanding of the cellular and molecular mechanisms for T cell help emerged. A subset of T cells, termed T follicular helper cells (T_FH cells), provides a helper function to B cells and represents one of the most numerous and important subsets of effector T cells in lymphoid tissues. T_FH cells are distinguishable from Th1 and Th2 cells by several criteria, including chemokine receptor expression (CXCR5), location/migration (B cell follicles), and function (B cell help). Central to the function of CD4⁺ T cells is IL-21, a “helper” cytokine produced by T_FH cells that potently stimulates the differentiation of B cells into Ab-forming cells through IL-21R. Consequently, dysregulation of T_FH cell function, and over- or under-expression of T_FH cell–associated molecules such as ICOS or IL-21, most likely contributes to the pathogenesis of certain autoimmune diseases or immunodeficiencies.