Immune-deficient mice are widely used in cancer research to study human cancer biology and evaluate new therapeutics. No comprehensive study has been published documenting differences in human tumor engraftment among immune-deficient strains. Using RhoC-expressing human (A375) melanoma cells, we evaluate scid, NOD-scid (NS), NOD-scid β2mnull (NSB), and NOD-scid IL2Rγnull (NSG) as xenograft tumor recipients. Bioluminescence, magnetic resonance imaging and histopathology were employed to monitor serial tumor growth. Melanoma metastases growth is delayed and variable in scid, and NS mice. In contrast, NSB and NSG mice show rapid tumor engraftment, although tumor growth is variable in NSB mice. NK cells were detected in all strains except NSG, and in vitro activated scid, NS and NSB NK cells kill human melanoma lines and primary melanoma cells. Expression of human NKG2D ligands, MICA and MICB, renders melanoma susceptible to murine NK cell-mediated cytotoxicity and killing is inhibited by antibody blockade of murine NKG2D. Murine NKG2D recognition of MICA/B is an important receptor-ligand interaction employed by NK cells in immune-deficient strains to limit engraftment of human tumors. The absolute NK deficiency in NOD-scid IL2Rγnull animals makes this strain an excellent recipient of melanoma and potentially other human malignancies.