We have used gene targeting in embryonic stem cells to generate mice with mutations in T-cell receptor (TCR) gene-α, TCR-β, TCR-δor the Recombination Activating Gene-1 (RAG-1). TCR-αor TCR-βmutant mice are deficient inαβT cells, but still containγδT cells and B cells. TCR-δmutant mice are deficient inγδT cells, but still containαβT cells and B cells. Mice doubly mutant for TCR-βand TCR-δdo not have any mature T cells, but still have B cells. RAG-1 mutant mice are totally deficient in both mature T cells and B cells. Here, I describe recent studies of thymocyte development in the mutant mice, and I review experiments addressing the function of the immune system of the mutant mice.