The molecular mechanisms by which tumours acquire resistance to antiangiogenic therapies — such as small-molecule receptor tyrosine kinase inhibitors (RTKIs) — remain poorly understood. Here, applying global transcriptomic, proteomic and metabolomic approaches to preclinical cancer models, the authors provide mechanistic insights into how tumours adapt their metabolism to antiangiogenic therapy. Following RTKI treatment withdrawal, tumours undergo a metabolic shift from a glycolytic phenotype towards lipid metabolism and increased TCA activity, which is associated with rapid tumour regrowth and accelerated metastatic dissemination. Inhibition of fatty acid synthase reversed this malignant adaptation and prevented tumour relapse, which may have clinical implications.