The CD300 family of molecules modulates a broad and diverse array of immune cell processes via their paired activating and inhibitory receptor functions. The description that CD300 molecules are able to recognize lipids, such as extracellular ceramide, phosphatidylserine, and phosphatidylethanolamine, that are exposed on the outer leaflet of the plasma membrane of dead and activated cells has opened a new field of research. Through their binding to lipids and other ligands, this family of receptors is poised to have a significant role in complex biological processes and in the host response to severe pathological conditions. Indeed, published data have demonstrated their participation in the pathogenesis of several disease states. Moreover, this family of receptors has great potential as targets for diagnosis and therapeutic purposes in infectious diseases, allergies, cancer, and other pathological situations. For instance, one member of the family, CD300a, has been studied as a possible biomarker. Here, a review is provided on the cellular distribution of the human and mouse families of receptors, the stimuli that regulate their expression, their ability to tune leukocyte function and immune responses, their signaling pathways, ligand recognition, and their clinical relevance.