Our understanding of NK biology has expanded immensely since the initial discovery of natural killer cells in 1975. New studies have uncovered various levels of immune regulation both on and by unique subsets of NK cells, which go well beyond simple receptor-ligand interactions between NK cells and target cancer cells. Distinct suppressor and effector populations of NK cells have been delineated in both viral and tumor models. Interactions between NK cells and dendritic cells, T cells, and B cells also dramatically alter the overall immune response to cancer. To exploit the diverse functional abilities of NK cell subsets for cancer immunotherapies, it is important to understand NK cell biology and NK regulator mechanisms.