The enzyme dihydroorotate dehydrogenase (DHODH) is essential for the de novo production of pyrimidines starting with the generation of uridine monophosphate (UMP), and small molecule inhibitors of DHODH are highly effective in vitro and in vivo in pre-clinical models of malignancy. DHODH is an unlikely cancer target, as it is ubiquitously expressed and is not known to be mutated or overexpressed in cancer. However, malignant cells seem to be more metabolically-dependent on de novo pyrimidine production, forming the potential basis of a therapeutic window. The use of DHODH inhibitors in solid tumor malignancies has been clinically disappointing. However, the use of DHODH inhibitors in the treatment of acute myeloid leukemia (AML) has been more recently shown to have both a cytotoxic and a pro-differentiation effect, making AML an attractive new disease indication. As of 2018, trials of DHODH inhibitors are underway, and will provide better insight into their potential utility in patients with hematologic malignancies. Historically, the use of small molecule inhibitors of DNA and RNA synthesis is common in cancer chemotherapy, and we have decades of experience with effective molecules such as 5-Fluorouracil, cytarabine, and methotrexate. Given the essential role of uridine monophosphate (UMP) in DNA and RNA synthesis, it is no surprise that multiple inhibitors of de novo pyrimidine synthesis have been identified as hits during in vitro cancer cell line screening efforts through the 1970s and 1980s. Indeed, inhibitors at every step of pyrimidine synthesis have been studied in clinical trials; N-(phosphonacetyl)-L-aspartate (PALA) as an inhibitor of the aspartate-transcarbamylase function of CAD, brequinar sodium as an inhibitor of DHODH, and pyrazofurin as an inhibitor of the orotate-phosphoribosyltransferase function of UMPS (Figure 1).