Natural Killer (NK) cells are innate immune cells equipped with the ability to rapidly kill stressed cells that are neoplastic or virally-infected. NK cells are especially important in settings where these stressed cells down-regulate MHC class I molecules and evade recognition by cytotoxic T cells. However, the activity of NK cells alone is often suboptimal to fully control tumor growth or to clear viral infections. Thus, the enhancement of NK cell function is necessary to fully harness their anti-tumor or anti-viral potential. TAM receptors (Tyro3, Axl, and Mer) are receptor tyrosine kinases (RTKs) that are expressed by multiple immune cells including NK cells. Although RTKs typically enhance cellular functions, TAM receptor ligation blocks NK cell activation. The mechanisms by which RTKs block NK cell signaling downstream of activating receptors are unknown. We demonstrate that TAM receptors attenuate NK cell responses via the activity of the E3 ubiquitin ligase Cbl-b. Specifically, we show that Tyro3, Axl, and Mer phosphorylate Cbl-b, and Tyro3 ligation activates Cbl-b by phosphorylating tyrosine residues 133 and 363. Ligation of TAM receptors by their ligand Gas6 suppresses activating receptor-stimulated NK cell functions, such as IFNγ production and degranulation, in a TAM receptor kinase- and Cbl-b-dependent manner. Moreover, Gas6 ligation induces the degradation of LAT1, a transmembrane adaptor protein required for NK cell activating receptor signaling, in WT but not in Cbl-b knock-out (KO) NK cells. Together, these results suggest that TAM receptors may attenuate NK cell function by phosphorylating Cbl-b, which in turn dampens NK cell activation signaling by promoting the degradation of LAT1. Our data, therefore, support a mechanism by which RTKs attenuate, rather than stimulate, signaling pathways via the activation of ubiquitin ligases. Based on our findings, the TAM/Cbl-b pathway has key molecules that can be targeted therapeutically for the treatment of cancers and viral infections. In collaboration with Progenra, Inc, we tested several novel small molecule inhibitors that target Cbl-b. Several of the inhibitors tested enhanced NK and T cell effector functions. One inhibitor tested in vivo did not have any effect in decreasing tumor burden, likely due to the poor half-life of the in vivo formulation. More inhibitors in development will be tested in the future. These inhibitors provide a promising novel therapeutic strategy to enhance NK and T cell activation in the setting of a variety of cancers and possibly chronic viral infections.