CD300 members, belonging to the receptor family mainly expressed on immune cell surfaces, recognize various ligands, such as phosphatidylserine [1], gangliosides [2], and lipopolysaccharides [3], transmitting inhibitory or activating signals. They play vital roles in regulating allergies, cancers, and inflammatory diseases [4], [5], [6]. CD300e, a transmembrane glycoprotein of myeloid cells, functions as an immune activation receptor in various pathophysiological processes, such as oxidative stress, innate and adaptive immune reactions, tissue damage and repair, and metabolism [7]. Emerging studies have implicated that CD300e plays critical roles in a variety of inflammatory and immune diseases, serving as a potential marker for disease diagnosis and treatment. This review summarizes currently available data regarding the biological effects and underlying mechanisms of CD300e in the regulation of inflammation and autoimmunity, providing insight into the pathogenesis and therapeutic strategies for these diseases.