Propranolol is a nonselective β-adrenergic receptor (AR) blocker that has been the first-line therapy for problematic infantile hemangioma (IH), the most frequent childhood vascular tumor. Although IHs are benign and eventually regress spontaneously, at least 15% of patients require treatment. Despite the extensive use of propranolol for IH treatment, its mode of action remains unclear. In this issue of the JCI, Seebauer et al. investigated the cellular and molecular consequences of propranolol treatment on IH vascular tumor formation in a murine model of IH. The efficacy of propranolol was independent of its β-AR blocker activity and was attributable to the direct targeting of the transcription factor SOX18, which, in turn, reduced hemangioma blood vessel formation. We believe these results will guide clinical translation for the use of more efficient and safer therapies for IH and possibly for other vascular anomalies in which SOX18 plays a role.