Although it is clear that natural killer (NK) cells have the ability to recognize and kill tumour cells in vitro, their potential as a highly effective treatment for tumours has not yet been realized in the clinical setting. Following activation, endogenous and adoptively transferred NK cells can be found in tumours. However, not all tumours are equally well-infiltrated, and many of the infiltrating cells do not make target-cell contact but rather reside in the tumour stroma. New insights into the migration of NK cells, their activation status and production of matrix-degrading proteases might help to overcome this localization defect, with implications for the treatment of human cancer.