Resting B cells can be stimulated to proliferate and differentiate to antibody-producing cells by the combination of cell contact and soluble signals provided by activated primed helper T (Th) cells. The ability of purified plasma membranes from activated Th cell clones and recombinant lymphokines to reconstitute B cell proliferation and differentiation has allowed an increased understanding of B cell activation and characterization of the molecules involved. B cell-Th cell contact appears sufficient for delivering the proliferative signal to B cells in the absence of lymphokines. A receptor ligand pair that plays a critical role in delivery of the contact signal is CD40 on the B cell surface and the ligand for CD40 on activated Th cells. Lymphokines alone do not drive resting B cell differentiation, however, when these soluble signals are delivered during the time of B cell DNA replication, they effect B cell differentiation and isotype switching. Delivery of the CD40-dependent contact signal to resting B cells appears to require a high degree of CD40 crosslinking on the B cell surface. Providing contact signals to naive B cells with recombinant molecules in membrane fractions may allow the generation of methodology to support the production of novel antibodies in vitro.