B lymphocytes with receptors specific for a particular hapten have been prepared through an antigen-affinity procedure. Methods have been developed for the clonal stimulation of these cells in vitro, with a single, hapten-specific B cell as the unequivocal target. Many stimulatory combinations involve multivalent antigen and one or more antigen non-specific, non-MHC restricted T lymphocyte-derived growth and differentiation factors. These factors, of which there are at least 4 or 5, are progressively being defined and should soon become available through recombinant DNA technology. Judicious use of factor combinations and selected antigens should soon answer whether "T-independent" and "T-dependent" B cells are truly separate subsets. A contact between multivalent antigen and immature B cell in the absence of these co-stimulatory factors can lead to the receipt and storage of a negative signal by the B cell. The B cell is not killed, but rather rendered anergic. Whether clonal anergy among B cells is an important mechanism in physiologic self-tolerance remains to be determined.