The mitochondrial enzyme MTHFD2, which is involved in one-carbon metabolism, has been shown to contribute to the progression of renal cell carcinoma (RCC). MTHFD2 expression was significantly increased in human RCC tissues and MTHFD2 knockdown considerably reduced xenograft tumour growth. MTHFD2 was found to have a crucial role in controlling global N6-methyladenosine methylation levels. It promotes the methylation of HIF2A mRNA, enhancing translation and promoting aerobic glycolysis. These data link one-carbon metabolism to HIF2α-dependent metabolic reprogramming in RCC. Furthermore, MTHFD2 and HIF2α promote metabolic reprogramming and tumour growth by forming a positive feedforward loop.