Natural killer (NK) cells are innate immune effector cells that make up approximately 10-15% of the peripheral blood lymphocytes in humans and are primarily involved in immunosurveillance to eliminate transformed and virally-infected cells. They were originally defined by their ability to spontaneously eliminate rare cells lacking expression of class I major histocompatibility complex (MHC-I) self molecules, which is commonly referred to as "missing self" recognition. The molecular basis for missing self recognition emerges from the expression of MHC-I-specific inhibitory receptors on the NK cell surface that tolerize NK cells toward normal MHC-I-expressing cells. By lacking inhibitory receptor ligands, tumor cells or virus-infected cells that have down-modulated surface MHC-I expression become susceptible to attack by NK cells. Killer cell Ig-like receptors (KIR; CD158) constitute a family of MHC-I binding receptors that plays a major role in regulating the activation thresholds of NK cells and some T cells in humans. Here, we review the multiple levels of KIR diversity that contribute to the generation of a highly varied NK cell repertoire and explain how this diversity can influence susceptibility to a variety of diseases, including cancer. We further describe strategies by which KIR can be manipulated therapeutically to treat cancer, through the exploitation of KIR/MHC-I ligand mismatch to potentiate hematopoietic stem cell transplantation and the use of KIR blockade to enhance tumor cell killing.