Oct-2, a POU homeodomain protein expressed primarily in B cells, is a powerful transcriptional activator that binds to DNA at sites appropriately placed for major effects on immunoglobulin gene expression. Our examination of B cell development and function in Oct-2 null mice did not support an essential role for Oct-2 early in B cell development. Rather, Oct-2 was required later, when B cells were induced to differentiate to antibody-secreting cells. We show here that Oct-2 is not required for normal immunoglobulin production by mature B lymphocytes. Instead, it is essential for a normal proliferative response to polyclonal mitogens. Responses to signals from activated T cells are unaffected. The requirement for Oct-2 maps to an early activation step in G1, during which B cells make the commitment to progress through the cell cycle and to divide.