Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein originally described as a binding partner of the p50 subunit of DNA polymerase δ and proliferating cell nuclear antigen. In addition to its role in DNA replication and damage repair, Poldip2 has been implicated in mitochondrial function, extracellular matrix regulation, cell cycle progression, focal adhesion turnover, and cell migration. However, Poldip2 functions are incompletely understood. In this review, we discuss recent literature on Poldip2 tissue distribution, subcellular localization, and function. We also address the putative function of Poldip2 in cardiovascular disease, neurodegenerative conditions and in renal pathophysiology.