The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. Display omitted •Antiangiogenic therapy withdrawal promotes tumor aggressiveness•Tumors shift their metabolism toward lipid synthesis after treatment withdrawal•Blocking lipid synthesis restores the beneficial effect of antiangiogenic drugs While antiangiogenic therapy blocks tumor growth, Sounni et al. show that, after withdrawal, tumors adapt their metabolism and boost lipid synthesis to drive rapid regrowth and metastasis. Pharmacological or genetic inhibition of lipogenesis in several cancer models counteracts tumor aggressiveness, revealing a key role for FASN in this adaptive response.