The field of immunotherapy is a continually expanding niche in cancer biology research. In the last two decades, there has been significant progress in identifying better targets and creating more specific agents for therapy in the field. B7-H3 (CD276) is an immune checkpoint from the B7 family of molecules, many of whom interact with known checkpoint markers including CTLA4, PD-1, and CD28. This is an exciting molecule that is overexpressed in many cancers, although the receptor of B7-H3 has not been characterized. Initially, B7-H3 was thought to co-stimulate the immune response, but recent studies have shown that it has a co-inhibitory role on T-cells, contributing to tumor cell immune evasion. Therefore, its overexpression has been linked to poor prognosis in human patients and to invasive and metastatic potential of tumors in in vitro models. Moreover, recent evidence has shown that B7-H3 influences cancer progression beyond the immune regulatory roles. In this review, we aim to characterize the roles of B7-H3 in different cancers, its relationship with other immune checkpoints, and its non-immunological function in cancer progression. Targeting B7-H3 in cancer treatment can reduce cell proliferation, progression, and metastasis, which may ultimately lead to improved therapeutic options and better clinical outcomes.