DNAX activation protein of 12kDa (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter, which couples to multiple receptors expressed on natural killer (NK) cells, monocytes, and neutrophils. Initially, DAP12-mediated signaling was mainly investigated downstream of receptors expressed on NK cells. In myeloid cells, one of the receptors associating with DAP12 is the triggering receptor expressed on myeloid cells (TREM)-1. Since the real nature of TREM-1L(s) is still illusive, TREM-1 biology was so far only studied using agonistic monoclonal antibodies for receptor ligation. Triggering via TREM-1 results in the production of pro-inflammatory cytokines, chemokines, reactive oxygen species (ROS), and leads to rapid degranulation of neutrophilic granules, and phagocytosis. Furthermore, application of a TREM-1/Ig fusion protein in an animal model of experimentally induced sepsis increases survival. It is obvious that targeting components of the TREM-1/DAP12 pathway could be a promising therapeutic strategy for the treatment of inflammatory diseases. Therefore, it is of great importance to get further insight into the signaling cascade downstream of TREM-1. This review summarizes the current understanding of the TREM-1/DAP12 pathway in monocytes and neutrophils.