TREM-1 (triggering receptor expressed on myeloid cells), a recently discovered receptor of the immunoglobulin superfamily, activates neutrophils and monocytes/macrophages by signaling through the adapter protein DAP12. TREM-1 is the best-characterized member of a growing family of DAP12-associated receptors that regulate the function of myeloid cells in innate and adaptive responses. TREM-1 amplifies Toll-like receptor-initiated responses against microbial challenges and potentiates the secretion of proinflammatory chemokines and cytokines in response to bacterial and fungal infections. Blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infections that cause systemic hyperinflammatory syndromes. The TREM-1 ligands are not known. Characterization of TREM-1 natural ligands will further illuminate the mechanisms regulating innate responses against pathogens. Whatever the ligands, targeted activation or blockade of TREM-1 and its ligands may help maximize the efficacy of existing treatments for sepsis.