Cancer cells often exhibit a reprogrammed metabolism to accommodate their higher proliferation rates. Serine is a building block for de novo nucleic acids synthesis, and cancer cells typically require more of it. PHGDH is the rate limiting enzyme in human serine synthesis steps and is often highly expressed in cancer. About a dozen PHGDH inhibitors have been reported, including three natural products, azacoccone E, ixocarpalactone A, and oridonin. The inhibition mechanism of most inhibitors is still lacking, and none of these inhibitors have entered clinical trials. In this commentary, we present new data on withaferin A, another natural product inhibitor of PHGDH, and discuss the inhibition mechanism by these natural products. The knowledge gained from these inhibitor studies may help guide the development of future PHGDHtargeted anticancer drugs.