B7-H3 (CD276), a newly identified member of the B7 family of molecules, is often induced in human tumors and its overexpression is closely correlated with survival, prognosis or tumor grade. Although cancer immunotherapy has not been completely translated into clinical successes, interest has been further enhanced by the realization of these costimulatory molecules' potential as targets to modulate clinical immune responses. Despite ample evidence implicating B7-H3 in tumor immune escape, a steady flow of reports have suggested that it may also have antitumor effects under certain circumstances. The safety and efficacy of targeting B7-H3 with a monoclonal antibody for the treatment of advanced-stage central nervous system cancer in children has been proven, making B7-H3 an attractive therapeutic target for this kind of tumor. In addition, B7-H3 was shown to promote invasion and accelerate carcinogenesis in tumor progression according to its nonimmunological regulatory roles. In this review, we discuss current understanding of the diverse functions of B7-H3 in carcinogenesis and cancer progression, and consider future directions for designing cancer immunotherapeutic agents targeting B7-H3.