In early seventies "natural killer (NK) cells", a third lymphocyte subset was discovered that revealed an unexpected ability to kill syngeneic and allogeneic tumor targets, thus emerging as the most potent non-specific cytotoxic cells in both human and mouse. Decades of research revealed the multifaceted nature of these cells. Now we know that NK cells are highly specific cells able to discriminate between self (which is spared) and non-self (which is attacked). Most of the specific and non HLA-specific surface receptors involved in NK cell recognition and function have been identified and, to date, only few of them still remain orphans. We also know that NK cells contribute to both innate and adaptive immune responses, interact with other immune cell types and release type 1 cytokines and chemokines. Moreover, fundamental data are accumulating on NK cell development and migration under both physiological and pathological conditions. The time is arrived to exploit these cells in the cure of cancer patients. While encouraging results emerged in hematological malignances, the road to treat solid tumors using NK cells is still covered by obstacles that hamper their function and that just begin to be unveiled.