Natural killer (NK) cells express numerous receptors, which continually engage with ligands on cell surfaces. Until 1995, only a handful of these receptors were characterized and the molecular basis of NK cell activation was obscure. Recently, considerable advances have been made in characterizing the receptor repertoire on human NK cells. Both activating and inhibitory receptors can transduce positive or negative signals to regulate NK cell cytotoxicity and cytokine release responses. The inhibitory receptors normally predominate in this balance of signals. Certain tumor cells and virally infected cells that lack major histocompatibility complex (MHC) class I molecules, however, can rapidly trigger NK cell activation. The basis of this activation is the loss of negative signals that are normally transmitted by MHC class I-binding inhibitory receptors, and the corresponding domination of activating receptor signals. While ligand specificity for a number of the recently described receptors is still a mystery, their signal transduction properties have begun to be defined. The dynamic crosstalk between these receptors ultimately governs the NK cell activation state. Although the complexities of NK cell signalling are only marginally understood, several overall themes have been defined by characterizing the roles of distinct pathways during NK cell responses.