Lack of functional expression of CD40 ligand (CD40L) on T cells results in hyper-IgM syndrome (HIGM1), a human immunodeficiency associated with a severely impaired humoral immune response that is consistent with defects in B-cell responses. Patients also succumb to recurrent opportunistic infections such as Pneumocystis carinii and Cryptosporidial diarrhoea, suggesting that T-cell functions are also compromised in these individuals, but so far this has not been explained. We have previously shown that mice deficient for CD40L, like HIGM1 patients, show grossly abnormal humoral responses. Here we report that CD40L-deficient mice are defective in antigen-specific T-cell responses. Adoptively transferred antigen-specific CD4+ T cells lacking CD40L failed to expand upon antigen challenge of the recipients, showing that expression of CD40L on T cells is required for in vivo priming of CD4+ T cells and therefore for the initiation of specific T-cell immune responses.