Abstract Infantile hemangioma (IH) is an extraordinary example of vascular overgrowth wherein vessels form rapidly over a year, then undergo a slow spontaneous involution that leaves behind a fibrofatty residuum. IH is common: it occurs in 5% of infants, equating to ~183,200 infants/year in the U.S. alone. 10-15% of IH will cause complications – e.g., destroy facial structures and impair vision, breathing and feeding depending on the location. Propranolol was discovered serendipitously to be effective therapy for IH, yet some do not respond, regrowth occurs in ~20% of cases, and surgery is needed in 37% of patients to correct IH residua. In the current funding cycle, we showed the non-beta blocker R+ enantiomers of propranolol and atenolol prevent hemangioma endothelial differentiation by directly interfering with the activity of the transcription factor SOX18 in hemangioma stem cells (HemSC). Further we showed that R+ propranolol and R+ atenolol, along with the small molecule SOX18 inhibitor Sm4, block hemangioma vessel formation in vivo in a pre-clinical model that uses IH patient derived HemSC. Our findings elucidate a novel etiological component of IH and also validate a molecular target, which opens new research directions for discovery and drug repurposing. Using R-propranolol as a molecular probe, we uncovered by transcriptional profiling of HemSC that the most decreased biological process during HemSC endothelial differentiation is the mevalonate pathway. From this data, we propose an entirely novel SOX18-mevalonate pathway axis as a central regulatory process that underpins IH-vascular overgrowth. We suggest a new conceptual framework and clinical research directions in which R+ propranolol, R+ atenolol, statins, or tipifarnib (all mevalonate pathway blockers) have the potential to be repurposed to prevent vascular overgrowth. This molecular strategy should reduce side effects seen with racemic (traditional) propranolol therapy due to beta-adrenergic receptor blockade and provide rapid clinical benefit, especially for non-responder patients. Our goals in this renewal are to decipher how the SOX18-mevalonate pathway contributes to IH formation and investigate the gene regulatory networks that govern the vasculogenic and adipogenic transitions. In addition, we aim to determine whether the SOX18-mevalonate axis is an etiological component in other vascular anomalies (VA), which could lead to repurposing these drugs to a wide range of VA.