Innate immune receptors represent important therapeutic targets for inflammatory disorders. In particular, the Toll-like receptor (TLR) family has emerged as a promoter of chronic inflammation that contributes to obesity, insulin resistance and atherosclerosis. Importantly, triggering receptor expressed on myeloid cells-1 (TREM-1) has been characterized as an 'amplifier' of TLR2 and TLR4 signaling. TREM-1- and TREM-2-dependent signaling, as opposed to TREM-like transcript-1 (TLT-1 or TREML1), are mediated through association with the transmembrane adaptor DNAX activation protein of 12 kDa (DAP12). Recessive inheritance of rare mutations in DAP12 or TREM-2 results in a disorder called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, and surprisingly these subjects are not immunocompromised. Recent progress into the roles of TREM/DAP12 signaling is critically reviewed here with a focus on metabolic, cardiovascular and inflammatory diseases. The expanding repertoire of putative ligands for TREM receptors is also discussed.