Immune homeostasis is achieved by balancing the activating and inhibitory signal transduction pathways mediated via cell surface receptors. Activation allows the host to mount an immune response to endogenous and exogenous antigens; suppressive modulation via inhibitory signaling protects the host from excessive inflammatory damage. The checkpoint regulation of myeloid cells during immune homeostasis raised their profile as important cellular targets for treating allergy, cancer and infectious disease. This review focuses on the structure and signaling of inhibitory receptors on myeloid cells, with particular attention placed on how the interplay between viruses and these receptors regulates antiviral immunity. The status of targeting inhibitory receptors on myeloid cells as a new therapeutic approach for antiviral treatment will be analyzed.