Blockade of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) has produced considerable therapeutic effect, but only in a fraction of patients, so more targets are being investigated. VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint that is broadly expressed within hematopoietic cells and multiple cancers (low expressing frequency on solid tumors), particularly those with a poor immunotherapy response rate. As a result, VISTA has been identified as an appealing target for immunotherapy, and several VISTA inhibitors are currently in clinical and preclinical trials. In this review, the structural features and binding partners of VISTA are summarized, and we describe the latest developments of monoclonal antibodies and small molecules targeting VISTA as well as possible future directions for development of therapies targeting VISTA.