The early events regulating antiviral CD4 responses were tracked using an adoptive transfer model. CD4+ T cell expansion was nonlinear, with a lengthy lag phase followed by 2 days of explosive proliferation. A small number of naive Ag-specific CD4+ T cells were found in nonlymphoid tissues and, in the 8 days following infection, the number of activated cells increased in all tissues analyzed, and their effector functions matured. Finally, we show that a naive mouse contains∼ 100 naive CD4+ precursor cells specific for a single epitope, a precursor frequency of∼ 10− 5, similar to that of naive CD8+ T cells, indicating that the∼ 50-fold difference in size of the two responses to virus infection is determined by something other than the number of precursor cells.