The activation of murine and human natural killer (NK) cells is regulated by families of receptors including the Ly49 and Killer immunoglobulin-like receptors, respectively, both of which contain activating and inhibitory members. The archetypal role of inhibitory Ly49 receptors is to attenuate NK cell responses to normal cells that express major histocompatibility complex (MHC) class-I molecules, in essence allowing for more robust responses to infected or cancerous cells that lack MHC-I on their cell surface. However, it is now evident that Ly49 receptors have an appreciably more sophisticated array of functions. In particular, some activating Ly49 receptors can bind directly to MHC-I-like viral gene products such as m157, whereas others recognize self-MHC-I but only in the presence of viral chaperones. Although Ly49 receptor recognition is centred on the MHC-I-like fold, these NK cell receptors can also engage related ligands in unexpected ways. Herein we review the varied strategies employed by Ly49 receptors to recognize both self and viral ligands, with particular emphasis on the recently determined mode of Ly49-m157 ligation, and highlight the versatile nature of this family in the control of viral infections.