Cluster of differentiation 27 (CD27) is a member of the tumour necrosis factor receptor superfamily and plays a key role in T-cell activation by providing a costimulatory signal. Bound to its natural ligand CD70, CD27 signalling enhances T-cell proliferation and differentiation to effector and memory T cells and therefore has potential as an immune modulatory target in cancer treatment. The CD27 agonistic antibody varlilumab showed promising efficacy in haematological as well as solid cancers. Current studies investigate the combination of the CD27 agonistic antibody varlilumab in combination with the PD1 axis targeting immune checkpoint inhibitors like nivolumab or atezolizumab. Further, CD70 expression is used as a therapeutic target for ADCs, antibodies inducing ADCC, as well as the immunological target for chimeric antigen receptor gene-modified T cells and specific dendritic cell vaccination. In line with this, targeting the CD27 axis was shown to be feasible and safe in early clinical trials with the most commonly occurring side effects being thrombocytopenia, fatigue and nausea.