Wong et al. report that metabolism — more specifically, fatty acid β-oxidation (FAO) — promotes lymphatic development. They found that FAO is high in lymphatic endothelial cells (LECs; which line lymph vessels) and that inhibition or LEC-specific loss of CPT1A, which is a rate-controlling enzyme of FAO, impaired the differentiation of LECs from their precursors, venous endothelial cells, both in vitro and in mice. The transcription factor PROX1 and vascular endothelial growth factor receptor 3 (VEGFR3) are known inducers of LEC differentiation through the upregulation of lymphatic genes. The authors report that PROX1 upregulates FAO by inducing CPT1A expression, thereby increasing the levels of FAO-derived acetyl-CoA, which is used by p300 to acetylate histone H3 at Lys9 at key lymphatic genes, including VEGFR3. Moreover, they propose that selective activation of lymphatic genes is enhanced through PROX1 binding to p300 and preferentially recruiting it to PROX1-target genes.