Phosphoglycerate dehydrogenase (PHGDH) is traditionally known for catalyzing the conversion of 3-phosphoglycerate (3-PG) to 3-phosphonooxypyruvate (3-PHP), a key step in the de novo synthesis of serine. However, recent studies have uncovered that PHGDH exhibits a wide range of non-canonical functions. In addition to its role in metabolic reactions within the glycolytic pathway, PHGDH also participates in the regulation of gene transcription and translation. These newly identified functions significantly alter our understanding of how PHGDH aberrantly regulates tumor cell fate. In this review, we summarize the mechanisms by which PHGDH promotes cancer progression through these non-canonical pathways, potentially offering new therapeutic avenues for cancer.