The recent identification of cancer-associated mutations in genes encoding metabolic enzymes has provided a direct link between altered metabolism and cancer. Mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Cells and tumours with impaired FH activity accumulate fumarate and constitutively express hypoxia-inducible factor {alpha} (HIFα). Regulation of HIFα is mediated post-translationally by prolyl hydroxylase (PHD) enzymes, which require iron, oxygen and 2-oxoglutarate (2OG) as substrates. Elevated intracellular fumarate competes with 2OG and inhibits PHD function, thus preventing the hydroxylation and subsequent degradation of HIFα. Previously we demonstrated in a murine model of HLRCC that hyperplastic renal cyst development is independent of the HIF/PHD pathway. Using the same model, we have identified novel genetic and metabolic pathways, potentially linking FH deficiency and renal cancer.