The innate immune system protects us from bacteria, viruses, and cancer. Natural killer (NK) cells are innate immune cells that can detect and destroy infected and tumour cells. How NK cells do this requires understanding of the molecules they use to sense what is harmless or dangerous, and how these molecules assist in the decision to ignore or kill the target cell. We have identified a receptor-ligand pair (NKR-P1B:Ocil/Clr-b) on NK cells and their targets, respectively, that mediates immune recognition at the molecular level. Because the NKR-P1B receptor is inhibitory, normal cells express the Ocil/Clr-b ligand to prevent NK cell attack, while infected and cancerous cells lose Ocil/Clr-b expression and are killed by NK cells. This suggests a role for the NKR-P1:Ocil/Clr interactions in fighting cancer and infectious disease. We will advance our understanding of NK-target interactions by studying how the NKR-P1:Ocil/Clr and other receptor-ligand pairs affect our immune defenses in fighting cancer and infection. We are currently studying the structure, function, and control of ligand expression, and how pathogens can evade this NK/immune recognition. This knowledge could lead to therapies in cancer treatment and control of infectious disease.