T-B cell interactions have a central role in the development of humoral immunity. The binding of a 39 kDa protein (gp39), selectively expressed on activated Th cells, to its receptor CD40, on B cells, results in the initial B cell activation. Thereafter, Th cell derived cytokines regulate the differentiation of B cells into antibody-forming cells. Most of these data are derived from in vitro experiments. This article discusses in vivo experiments dealing with T-B interactions. First, the immunohistochemical analysis of T cell activation (gp39 expression), cytokine and antibody production in murine spleens after injection of model antigens (TNP-Ficoll, TNP-KLH, and rabbit anti-IgD antibodies). Second, the in vivo role of gp39 and cytokines in these immune responses. Finally, by combining these in vivo experiments with in vitro data we present an in vivo model for T cell dependent antibody responses.