NK (natural killer) cells are lymphocytes of the innate immune system that are involved in early defense mechanisms against foreign cells as well as autologous cells that are undergoing various forms of stress, such as microbial infection (viral, bacterial, or parasitic), tumor transformation, or nonmalignant activation. NK cell activation is controlled by a dynamic balance between complementary and antagonist pathways that are initiated when they bind a cell targeted for destruction. The Natural Killer Cell Signaling Pathway illustrates the signals produced by the activating cell surface receptors that initiate PTK (protein tyrosine kinase)-dependent pathways through their noncovalent association with transmembrane signaling adaptors that harbor ITAMs (immunoreceptor tyrosine-based activation motifs). This Connections Map also describes the mechanism by which these positive pathways are antagonized by intracytoplasmic PTPs (protein tyrosine phosphatases) that are activated upon engagement of cell surface receptors with intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). The tyrosine phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways. Additional cell surface receptors that are not directly coupled to ITAMs also participate in NK cell activation, such as NKG2D (which is noncovalently associated with the DAP10 transmembrane signaling adaptor), adhesion molecules, and cytokine receptors. Understanding the integration of these signals into the "canonical" PTK-PTP equilibrium represents the future challenge for the elucidation of NK cell effector signaling pathways.