My research program focuses on the biology of human natural killer (NK) cells and how NK cells control various disease processes and affect clinical outcomes. Our work describing interactions between KIR receptors and their HLA class I ligands have defined NK populations with hierarchical activity, and we have shown how the polymorphic genetic loci encoding KIR and HLA molecules can be used to predict NK activity in clinical settings such as allogeneic hematopoietic cell transplantation for leukemia. One of our longstanding research goals is to define the KIR/HLA genotypes and allotypes predictive of the greatest NK alloreactivity in hematopoietic cell transplantation, leading to lower leukemic relapse rates, lower transplant-related morbidity, and improved survival. Results from these studies will help transplant physicians further refine selection of HLA-compatible hematopoietic stem cell donors by considering donor KIR genotypes. We have broadened our research questions to include defining the role of NK cells in solid tumor control and viral infection, where KIR and HLA genotypes not only serve as markers for clinical outcomes but offer further insights to hierarchical control of NK effects. Understanding how human NK cells behave at rest and in disease states is critical to the ultimate goal of harnessing their innate capacity for recognition and eradication of tumors and virally-infected cells.