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[Abstract] Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria ; [Author summary] The coexistence within the same tumor of a variety of subpopulations, featuring different phenotypes (intra-tumoral heterogeneity) represents a challenge for diagnosis, prognosis and targeted therapies. In this work, we have explored the metabolic differences underlying tumor heterogeneity by building cell-type-specific genome-scale metabolic models that integrate transcriptome and metabolome data of two clonal subpopulations derived from the same prostate cancer cell line (PC-3). These subpopulations display either highly proliferative, cancer stem cell (PC-3/M) or highly invasive, epithelial-mesenchymal-transition-like phenotypes (PC-3/S). Our model-driven analysis and experimental validations have unveiled a differential utilization of the long-chain fatty acids pool in both subpopulations. More specifically, our findings show an enhanced entry of long-chain fatty acids into the mitochondria in PC-3/M cells, while in PC-3/S cells, long-chain fatty acids are used as precursors of eicosanoid metabolism. The different utilization of long-chain fatty acids between subpopulations endows PC-3/M cells with a highly proliferative phenotype while enhances PC-3/S invasive phenotype. The present work provides a tool to unveil key metabolic nodes associated with tumor heterogeneity and highlights potential subpopulation-specific targets with important therapeutic implications ; This work was supported by the European Commission Seventh Framework Programme FP7 (METAFLUX-Marie Curie FP7-PEOPLE-2010 ITN-264780); the Spanish Government and the European Union FEDER funds (SAF2014-56059-R, SAF2015-70270-REDT and SAF2015-66984-C2-1-R); Generalitat de Catalunya-AGAUR (2014SGR1017, xarxa de referència en biotecnologia, (TMT) and the support received through the prize "ICREA Academia" for excellence in research (MC), the Lendület Program of the Hungarian Academy of Sciences (BP) and the Welcome Trust (BP) ; Peer reviewed