The function of CD40 and its ligand (CD40L;gp39) has provided a molecular understanding for cognate interactions and the basis for hyper IgM syndrome. Studies using an antibody that neutralizes gp39 function in vivo have demonstrated that interactions between CD40 and gp39 are essential for primary and secondary thymus-dependent humoral immune responses, as well as for the generation of memory B cells. In addition, gp39 is critical for B cells to upregulate important costimulatory molecules and acquire professional antigen-presenting cell status. If B cells do not receive the gp39 signal, they are rendered tolerogenic for T cells. Finally, gp39-CD40 interactions are important in thymic education since blockade of this interaction interrupts negative selection.