Negative regulation of intracellular signaling delivered by the antigen receptors and coreceptors plays an important role in lymphocyte development and activation. Recent data from our laboratory and others have identified the Cbl family of ubiquitin ligases as important negative regulators in both T-cell and B-cell antigen receptor and coreceptor signaling. We show that c-Cbl and Cbl-b, two members of the Cbl family of proteins, play a redundant role in establishing the major histocompatibility complex-dependent development of thymocytes and in thymic selection. They also control the activation threshold and CD28 costimulatory signaling in peripheral T cells. In B cells, c-Cbl and Cbl-b set the B-cell receptor signaling threshold critical for proper B-cell maturation and anergy induction. Biochemical studies indicate that the immune regulation by Cbl proteins correlate with their ubiquitin ligase function. Inactivation of Cbl-b also renders mice resistant to both transplanted and spontaneous tumors due to an enhanced anti-tumor immunity of CD8(+) T cells. These findings thus place Cbl proteins at the center of a complex immune network regulation and suggest that modulation of this signaling pathway may be beneficiary to the treatment of autoimmunity and cancer.