Natural killer cells remained mysterious for many years after their discovery in the mid-1970s. Only in the late 1980s to early 1990s, the inspiring “missing self” hypothesis and the subsequent characterization of HLA class I-specific inhibitory receptors (KIRs and CD94/NKG2A) and activating receptors (mainly NKp46, NKp44, NKp30, and NKG2D), which mediate tumor or virus-infected cell recognition and killing, clarified the basic molecular mechanisms regulating NK cell functions. These discoveries paved the way for important progress in basic, translational, and clinical research. The most resounding success was their application to the therapy of high-risk leukemias in the haploidentical hematopoietic stem cell transplantation setting. The discovery of activating KIRs and subsequent studies of KIR genes led to novel paradigms on the organization of receptor-encoding genes. Several additional NK receptors, either inhibitory or activating, were discovered. Most receptor ligands were identified as well. In addition, functional studies revealed important crosstalk between NK and other immune cells, primarily dendritic cells. The strong cytolytic activity and the unique properties of NK cells prompted the design of novel strategies for their exploitation in immunotherapy, e.g., monoclonal antibodies allowing efficient triggering of NK cells against tumor cells, the use of engagers (i.e., BiKEs and TriKEs), or NK cells armed with chimeric antigen receptors. Therefore, it is conceivable that NK cells will soon represent an important resource in tumor immunotherapy.