The ability of natural killer (NK) cells to secrete lymphokines confers upon them the potential to regulate cell types via mechanisms other than direct cytotoxicity. During the past few years increasing evidence has been accumulating to show that NK and B cells can interact productively. First, NK cells cocultured with B cells can induce them to initiate polyclonal Ig secretion. This help is mediated by a soluble factor (or factors) that appears to be different from any known cytokine. Second, preactivated B lymphocytes can induce NK cells to produce greater amounts of IFN-gamma via an interaction that requires direct cell contact. Third, in contrast to previous suggestions, NK cells do not have the ability to kill primary B lymphocytes regardless of their stage of differentiation. Evaluation of the in vivo relevance of these interactions revealed that activated NK cells can increase the IgG2a response to a specific protein antigen. Without activation, NK cells neither enhance nor inhibit B cell responses to antigens. The deviation of the isotype distribution may allow increased NK cell specificity for certain pathogens by enhancing antibody-dependent cytotoxicity.