Natural killer (NK) cells control the early phases of viral infections, modulate antigen-specific immune responses, and participate in the rejection of tumours and bone marrow grafts. A fine balance between inhibitory and activating receptors tightly regulates NK cell activation. Biochemical studies in human cell lines and primary cells have revealed some of the activating NK cell signalling pathways, however animal models are instrumental to understand the physiological implications of these findings for immune responses in vivo. Gene targeting in mice and biochemical studies in cells are helping to dissect out the various signal transduction pathways that control NK cell activation. A clearer view of these pathways may eventually help designing more effective immune therapies based on the use of NK cells.