CBL-B, a RING finger E3-ubiquitin ligase, acts as an intracellular checkpoint and a regulator of cytotoxic lymphocytes and NK cells. CBL-B binds E2-ubiqutin as well as target proteins such as TAM receptor TYRO3, forcing further degradation of TYRO3. CBL-B modulates innate immune responses and plays a key role in host defense to pathogens and anti-tumor immunity. Targeting CBL-B represents a potential therapeutic strategy for the management of human immune-related disorders such as autoimmune diseases, infections, tumors, and allergic airway inflammation. CBL-B has emerged as a new target of interest in the field of immunotherapy due to its ability to suppress cancer immune-evasion. CBL-B initiates anti-cancer immune responses in NK cells in both cytotoxic and effector T cells, promoting T-cell and NK cell activation.