Studies of polyclonal and antigen-specific activation of B lymphocytes were compared to generate a model that addresses the roles of ligand-surface (s) IgD and ligand-sIgM interactions as well as the roles of antigen-specific, T cell-mediated help and nonspecific helper lymphokines in the activation of mature, resting B lymphocytes. The major features of the model are 1) cross-linking of sIg renders B cells more receptive to T cell help; 2) DNA synthesis in activated B cells can be induced by weak sIg cross-linking signals in the presence of antigen-specific T cell help or by stronger sIg cross-linking signals in the absence of help; 3) sIgD has a more dominant role than sIgM in direct, sIg-mediated B cell activation whereas sIgM has a more dominant role than sIgD in focusing antigen-specific T cell help onto activated B cells; 4) the loss of sIgD from activated B cells limits the transmission of sIg-mediated signals that can inhibit the differentiation of B cells into antibody-secreting cells; and 5) the cross-linking of sIg, the focusing of antigen-specific T cells, and nonspecific helper lymphokines are all required for induction of rapid, effective antibody responses against bacterial pathogens.