B cells are essential for humoral immunity, but the role that they have in regulating CD4+ T cell responses remains controversial. However, new data showing that the transient depletion of B cells potently influences the induction, maintenance and reactivation of CD4+ T cells, with the recent identification of antibody-independent functions of B cells, have reinvigorated interest in the many roles of B cells in both infectious and autoimmune diseases. In this Review, we discuss recent data showing how effector and regulatory B cells modulate CD4+ T cell responses to pathogens and autoantigens. © 2010 Macmillan Publishers Limited. All rights reserved.