Innate immune cells express a plethora of inhibitory receptors, many of which recognize molecular patterns. An appropriate balance between signaling via activating and inhibitory pattern recognition receptors is important for a proper immune response while preventing immunopathology. V-set and transmembrane domain containing 1 (VSTM1), also known as signal inhibitory receptor on leukocytes-1 (SIRL-1), is an inhibitory receptor expressed on myeloid cells. VSTM1 can modulate the function of myeloid cells, by inhibiting reactive oxygen species and neutrophil extracellular trap formation. VSTM1 recognizes shared molecular patterns both from endogenous and microbial origin, defining it as an inhibitory pattern recognition receptor. VSTM1 is involved in various pathological conditions, including autoimmune disorders and cancer, and its restricted expression on myeloid cells highlights its potential as a specific therapeutic target. This review summarizes the characteristics and function of VSTM1 in health and disease.