Casitas B cell lymphoma-b (Cbl-b) is a vital negative regulator of TCR and BCR signaling pathways, playing a significant role in setting an appropriate threshold for the activation of T cells and controlling the tolerance of peripheral T cells via a variety of mechanisms. Overexpression of Cbl-b leads to immune hyporesponsiveness of T cells. Conversely, the deficiency of Cbl-b in T cells results in markedly increased production of IL-2, even in the lack of CD28 costimulation in vitro. And Cbl-b-/- mice spontaneously reject multifarious cancers. Therefore, Cbl-b may be associated with immune-mediated diseases, and blocking Cbl-b could be considered as a new antitumor immunotherapy strategy. In this review, the possible regulatory mechanisms and biological potential of Cbl-b for antitumor immunotherapy are summarized. Besides, the potential roles of Cbl-b in immune-mediated diseases are comprehensively discussed, with emphasis on Cbl-b immune-oncology agents in the preclinical stage and clinical trials.