The severe combined immunodeficient (SCID) mouse has no adaptive immunity, lacking mature T and B cells in the peripheral blood or the lymphoid organs. It has been used extensively in biomedical research as a valuable translational model for xeno-engraftment of human tissues and cells. This review focuses on the engraftment of human peripheral blood cells and tissues in SCID mice, as well as in the newly established and more permissive SCID mice deficient in the IL-2 receptor gamma-chain. Human immune responses could be elicited and assessed in these humanized SCID mice upon vaccination or sensitization with allogeneic tissues. A translational model is proposed to attain preclinical data for testing human vaccines.