Cancers are complex diseases largely characterized by rapid cellular proliferation. This can be slowed by regulated cell death mechanisms like ferroptosis. Ferroptosis is triggered by extensive peroxidation of cell membrane phospholipids by reactive oxygen species (ROS), but ferroptosis can be inhibited by enzymes that undo peroxidation like GPX4. Another enzyme, DHODH, supports GPX4 and is vital to the production of pyrimidine nucleotides, critical building blocks for rapidly proliferating cells. In theory, this would make inhibiting DHODH a valuable therapeutic target for cancer by freeing up ferroptosis and hampering proliferation. However, this is complicated by the “Warburg effect,” which is common in some cancer cells. The Warburg effect is a shift away from using mitochondria for energy to other metabolic processes, which has knock-on effects. Mitochondria are an important part of the ROS generation needed to trigger ferroptosis, and studies have suggested that DHODH plays a key role in that mitochondrial ROS production. Some reports also suggested that inhibiting DHODH may also increase levels of glutathione, which makes GPX4 more efficient and further blocks ferroptosis. Thus, to fully understand the efficacy of DHODH inhibitors, researchers need to further examine how DHODH functions in cancer cells under the Warburg effect.