Two groups have found that the gene encoding the metabolic enzyme phosphoglycerate dehydrogenase (PHDGH), which is involved in serine biosynthesis, is essential in some cancer cells, thereby identifying the serine synthesis pathway as a new potential drug target in cancer. Working with a human breast cancer cell line, Possemato et al. devised an in vivo short hairpin RNA screen to test whether individual candidate metabolic oncogenes are required for tumor formation. From 133 candidates prioritized for screening using bioinformatics, 16 hits were identified. One, PHGDH, was studied further because it had been found to be frequently amplified in previous studies of breast cancer and melanoma tissue. Locasale et al. uncovered the importance of serine synthesis and PHGDH using a quantitative metabolic labeling approach. Both groups verified that overexpression of PHGDH is sufficient to drive serine synthesis and required for proliferation of cancer cell lines. Possemato et al. suggest that the oncogenic potential of PHGDH is due in part to its effects on other metabolites in the serine synthesis pathway, such as α-ketogluterate, although other mechanisms may be involved because Locasale et al. did not observe changes in α-ketogluterate levels. Together these studies reveal how genetic changes to a metabolic gene can promote disease. (Nature 476, 346–350, 2011; Nat. Genet. advance online publication, doi:10.1038/ng.890, 31 July 2011)