Progress in the field of NK cell receptors (NKRs) and their ligands has revolutionized our concept of how NK cells selectively recognize and lyse tumor while sparing normal cells. Major families of NKRs that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulin-like receptors (KIRs), C-type lectins, and natural cytotoxicity receptors. Identification of NK receptor ligands such as HLA, MHC class I chain-related genes A and B – MICA/B, etc. further clarifies the role of NKR/ligand interactions in NK cell function. Given the extensive genomic diversity of KIRs, HLA and MIC, it is reasonable to imagine that genotypes encoding imbalanced inhibitory and activating interactions may contribute to susceptibility or resistance to human diseases, including cancers. This review will discuss two cell-surface receptor/ligand systems involved in NK cell recognition of tumor targets – KIR/HLA and NKG2D/MIC and the potential relevance of their genetic polymorphism in malignancies.