Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the actions are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, named TAM. Their regulatory roles are prominent in the mature immune, reproductive, hematopoietic, vascular, and nervous systems. Gas6 /TAM system plays a role in the regulation of inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Deficiencies in TAM signaling are thought to contribute to chronic inflammatory and autoimmune disease in humans, and aberrantly elevated TAM signaling is strongly associated with cancer progression, and metastasis. We review the function of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of different diseases.