Gas6 and protein S are two homologous secreted proteins that depend on vitamin K for their execution of a range of biological functions. A discrete subset of these functions is mediated through their binding to and activation of the receptor tyrosine kinases Axl, Sky and Mer. Furthermore, a hallmark of the Gas6–Axl system is the unique ability of Gas6 and protein S to tether their non receptor-binding regions to the negatively charged membranes of apoptotic cells. Numerous studies have shown the Gas6–Axl system to regulate cell survival, proliferation, migration, adhesion and phagocytosis. Consequently, altered activity/expression of its components has been detected in a variety of pathologies such as cancer and vascular, autoimmune and kidney disorders. Moreover, Axl overactivation can equally occur without ligand binding, which has implications for tumorigenesis. Further knowledge of this exquisite ligand–receptor system and the circumstances of its activation should provide the basis for development of novel therapies for the above diseases.