The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptor-associated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors expressed in both lymphoid and myeloid lineages. We review here the main features of KARAP/DAP12, describing findings from its identification to recently published data, showing its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/macrophages and dendritic cells. Finally, bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals, as shown by the analysis of KARAP/DAP12-deficient mice and KARAP/DAP12-deficient Nasu-Hakola patients.