Pyrroline-5-carboxylate reductase (PYCR), the last enzyme in proline synthesis that converts P5C into proline, was found promoting cancer growth and inhibiting apoptosis through multiple approaches, including regulating cell cycle and redox homeostasis, and promoting growth signaling pathways. Proline is abnormally up-regulated in multiple cancers and becomes one of the critical players in the reprogramming of cancer metabolism. As the last key enzymes in proline generation, PYCRs have been the subject of many investigations, and have been demonstrated to play an indispensable role in promoting tumorigenesis and cancer progression. In this article, we will thoroughly review the recent investigations on PYCRs in cancer development.