The tetraspan plasma membrane protein PERP (p53 apoptosis effector related to PMP22) is a lesser-known transcriptional target of p53 and p63. A member of the PMP22/GAS3/EMP membrane protein family, PERP was originally identified as a p53 target specifically trans-activated during apoptosis, but not during cell-cycle arrest. Several studies have since shown downregulation of PERP expression in numerous cancers, suggesting that PERP is a tumour suppressor protein. This review focusses on the important advances made in elucidating the mechanisms regulating PERP expression and its function as a tumour suppressor in diverse human cancers, including breast cancer and squamous cell carcinoma. Investigating PERP's role in clinically-aggressive uveal melanoma has revealed that PERP engages a positive-feedback loop with p53 to regulate its own expression, and that p63 is required beside p53 to achieve pro-apoptotic levels of PERP in this cancer. Furthermore, the recent discovery of apoptosis-mediating interaction of PERP with SERCA2b at the plasma membrane-endoplasmic reticulum interface demonstrates a novel mechanism of PERP stabilisation, and how PERP can mediate Ca 2+ signalling to facilitate apoptosis. The multi-faceted role of PERP in cancer, involving well-documented functions in mediating apoptosis and cell-cell adhesion is discussed, alongside PERP's emerging roles in epithelial-mesenchymal transition, and PERPcrosstalk with inflammation signalling pathways, and other signalling pathways. The potential for restoring PERP expression as a means of cancer therapy is also considered.