Effective B cell–mediated immunity and antibody responses often require help from CD4⁺ T cells. It is thought that a distinct CD4⁺ effector T cell subset, called T follicular helper cells (T_FH), provides this help; however, the molecular requirements for T_FH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4⁺ T cells is both necessary and sufficient for in vivo T_FH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits T_FH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that T_FH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in T_FH differentiation.