CD155 (PVR/necl5/Tage4), a member of the nectin-like family of adhesion molecules, is highly upregulated on tumor cells across multiple cancer types and has been associated with worse patient outcomes. In addition to well described cell-intrinsic roles promoting tumor progression and metastasis, CD155 has now been implicated in immune regulation. The role of CD155 as a potent immune ligand with diverse cell-extrinsic functions is now being defined. CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96, which are differentially regulated at the cell surface on T cells and NK cells. The integration of signals from CD155 cognate receptors modifies the activity of tumor-infiltrating lymphocytes in a context-dependent manner, making CD155 an attractive target for immune-oncology. Preclinical studies suggest that targeting this axis can improve immune-mediated tumor control, particularly when combined with existing anti-PD-1 checkpoint therapies. In this review, we discuss the roles of CD155 on host and tumor cells in controlling tumor progression and discuss the possibility of targeting CD155 for cancer therapy.