Current insights into the molecular specificities that regulate natural killer (NK)-cell function suggest that it might be possible to design NK-cell-based immunotherapeutic strategies against human cancer. Here, we describe evidence for NK-cell targeting of human tumours and address crucial questions that, in our opinion, require consideration for the development of successful NK-cell-based therapies. Appropriately used, we predict that NK cells will have a role, both directly and in combination with other treatment modalities, in future treatment of cancer.