Protective immunity against a variety of infections depends on the amplification and differentiation of rare naïve antigen-specific CD4 and CD8 T cells. Recent evidence indicates that the clonotypic composition of the responding T-cell compartment has a critical role in the immune defense against pathogens. The present review compares and contrasts how naive CD4 and CD8 T cells recognize their cognate antigen, and discusses the factors that regulate the genesis and maintenance of the CD4 and CD8 T-cell receptor repertoire diversity.