Natural killer (NK) cells are important for early immune responses to viral infections and cancer. Upon activation, NK cells secrete cytokines and chemokines, and kill sensitive target cells by releasing the content of cytolytic granules. This unit is focused on the signal transduction pathways that regulate NK cell activities in response to contact with other cells. We will highlight signals regulating NK cell adhesion to target cells and describe the induction of cellular cytotoxicity by the engagement of different NK cell activation receptors. Negative signaling induced by inhibitory receptors opposes NK cell activation and provides an important safeguard from NK cell reactivity toward normal, healthy cells. We will discuss the complex integration of the different signals that occur during interaction of NK cells with target cells. Curr. Protoc. Immunol. 90:11.9B.1‐11.9B.17. © 2010 by John Wiley & Sons, Inc.