Although some tumour cells have normally functioning mitochondria and use oxidative metabolism to generate precursors (such as citrate) for the synthesis of macromolecules (such as lipids), it is unknown how tumour cells that carry mutations in components of the citric acid cycle or electron transport chain (ETC) produce such precursors. Mullen et al. show that tumour cells with mutations in complex I or complex III of the ETC use glutamine-dependent reductive carboxylation to form citrate using mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent isocitrate dehydrogenase. Patient-derived renal carcinoma cells with mutations in fumarate hydratase also use this metabolic pathway to support their growth, as do tumour cells with normal mitochondria treated with pharmacological ETC inhibitors.