The activation of B cells to proliferate and secrete Ig is finely regulated by T cells and, at least under in vitro conditions, by T-cell products. In order to study the molecular mechanisms underlying the regulatory events, an adequate number of normal B cells at distinct stages of activation and lymphokine responsiveness must be obtained. This can be achieved by activation via the Ig receptor. Using this system, the following conclusions can be drawn. Induction of proliferation via the Ig receptor is a transient event. Proliferation can be maintained only if both the anti-Ig signal and B-cell growth factors are provided. Ig secretion can be induced by lymphokines in mu + delta + B cells stimulated by anti-mu or kappa, while mu + delta + B cells stimulated to proliferate by anti-delta need helper T cells for Ig secretion. In the nu/nu sheep red blood cell system, induction of hypomethylation of DNA is insufficient to lead to Ig secretion, but hypomethylation induced by azacytidine enhances an otherwise suboptimal induction of Ig secretion by lymphokines.