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We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS‐KO) mice, the IFN‐γ response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS‐negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen‐specific B cells is impaired in ICOS‐KO mice, as is the generation of secondary antibody‐secreting cells. Analysis of endogenous CD4 memory cells in ICOS‐KO mice, using MHC class II tetramers, reveals normal primary clonal expansion, formation of memory clones and long‐term (10 wk) survival of memory cells, but defective expansion upon …