This study tracks the fate of antigen‐reactive B cells through follicular and extrafollicular responses and addresses the function of CD40 in these processes. The unique feature of this system is the use of transgenic B cells in which the heavy chain locus has been altered by site‐directed insertion of a rearranged V_H DJ_H exon such that they are able to clonally expand, isotype‐switch and follow a normal course of differentiation upon immunization. These Ig transgenic B cells when adoptively transferred into non‐transgenic (Tg) mice in measured amounts expanded and differentiated distinctively in response to T cell‐independent (TI) or T cell‐dependent (TD) antigens. The capacity of these Tg B cells to faithfully recapitulate the humoral immune response to TI and TD antigens provides the means to track clonal B cell behavior in vivo. Challenge with TI antigen in the presence of agonistic anti‐CD40 mAb resulted in well‐defined alterations of the TI response. In vivo triggering of Tg B cells with TI antigen and CD40 caused an increase in the levels IgG produced and a broadening of the Ig isotype profile, characteristics which partially mimic TD responses. Although some TD characteristics were induced by TI antigen and CD40 triggering, the Tg B cells failed to acquire a germinal center phenotype and failed to generate a memory response. Therefore, TD‐like immunity can be only partially reconstituted with CD40 agonists and TI antigens, suggesting that there are additional signals required for germinal center formation and development of memory.