Over the years, the enigmatic lifestyle of natural killer (NK) cells has fascinated immunologists. Elucidating the principles governing NK cell biology is a constant source of surprise, as these lymphocytes often break the rules of lymphocyte 'behavior' established by their T and B cell counterparts. In this Focus issue, experts address how NK cells have secured a fundamental place in the immune system, how they 'see' their targets and how they participate in and influence immune responses. We now need to understand how environmental 'niches' condition the generation and function of distinct NK cell subsets in vivo. Ultimately, we can hope that unraveling the mysteries of how these atypical lymphocytes function will have an impact on human disease therapies.