The Tumor protein D52 (TPD52) gene was identified nearly 20 years ago through its overexpression in human cancer, and a substantial body of data now strongly supports TPD52 representing a gene amplification target at chromosome 8q21.13. This review updates progress toward understanding the significance of TPD52 overexpression and targeting, both in tumors known to be characterized by TPD52 overexpression/amplification, and those where TPD52 overexpression/amplification has been recently or variably reported. We highlight recent findings supporting microRNA regulation of TPD52 expression in experimental systems and describe progress toward deciphering TPD52's cellular functions, particularly in cancer cells. Finally, we provide an overview of TPD52's potential as a cancer biomarker and immunotherapeutic target. These combined studies highlight the potential value of genes such as TPD52, which are overexpressed in many cancer types, but have been relatively understudied.