It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the “mesenchymal metabolic signature” (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits. Display omitted •Mesenchymal-like cancer cell lines express a common metabolic gene signature•Mesenchymal metabolic signature (MMS) genes are upregulated during the EMT•The pyrimidine degradation enzyme DPYD is essential for the EMT•Accumulation of DPYD products is essential for the EMT A set of metabolic genes is upregulated in high-grade cancers, including a pyrimidine degradation enzyme whose enzymatic activity and products—the dihydropyrimidines—are essential for EMT. The findings expand the remit of metabolic processes in cancer from simply fueling proliferation to driving transitions to aggressive states.