CD27 is a transmembrane phosphoglycoprotein costimulatory receptor belonging to the TNF family, and it is expressed on thymocytes, naïve T cells, B cells, and NK cells. CD27 binds to CD70, which is expressed in response to antigen stimulation. CD27-CD70 signaling leads to activation and differentiation of T cells into both memory and effector cells, and also stimulates B cells. CD27 can also bind to TRAFs 2 and 5 signaling through the NF-kß pathway. It is essential for the generation of T-cell memory, and co-stimulation of CD27 is believed to improve antiviral T-cell immunity. Altering CD27 signaling is thus of interest in various cancer, autoimmune, and viral immunotherapies. In immune checkpoint therapies, CD27 agonists are of interest often in combination with anti-PD-1 or anti-CTLA-4 agents, for example. Identifying CD27-phenotype tumors is important, as cancers that express CD27 have the potential for a more favorable outcome through treatment.