Proline metabolism features prominently in the unique metabolism of cancer cells. Proline biosynthetic genes are consistently upregulated in multiple cancers, while the proline catabolic enzyme proline dehydrogenase has dual, context-dependent pro-cancer and pro-apoptotic functions. Furthermore, the cycling of proline and Δ-pyrroline-5-carboxylate through the proline cycle impacts cellular growth and death pathways by maintaining redox homeostasis between the cytosol and mitochondria. Here we focus on the last enzyme of proline biosynthesis, Δ-pyrroline-5-carboxylate reductase, known as PYCR in humans. PYCR catalyzes the NAD(P)H-dependent reduction of Δ-pyrroline-5-carboxylate to proline and forms the reductive half of the proline metabolic cycle. We review the research on the three-dimensional structure, biochemistry, inhibition, and cancer biology of PYCR. To provide a global view of PYCR gene upregulation in cancer, we mined RNA transcript databases to analyze differential gene expression in 28 cancer types. This analysis revealed strong, widespread upregulation of PYCR genes, especially PYCR1. Altogether, the research over the past 20 years makes a compelling case for PYCR as a cancer therapy target. We conclude with a discussion of some of the major challenges for the field, including developing isoform-specific inhibitors, elucidating the function of the long C-terminus of PYCR1/2, and characterizing the interactome of PYCR.