Advances in molecular genetics have profoundly changed the understanding and management of congenital vascular malformations (CVM). Somatic mutations affectingthe PI3K/AKT/mTOR and RAS/MAPK signaling pathways (e.g., PIK3CA, AKT1, MTOR, KRAS, NRAS, MAP2K1) are now recognized as key drivers of CVM pathogenesis. Next-generation sequencing (NGS) and advanced molecular diagnostics allow precise identification of these mutations, enabling patient-tailored therapies. Clinical studies with sirolimus and alpelisib have shown significant radiologic and symptomatic improvements in slow-flow malformations, with manageable toxicity. FDA approval of alpelisib for PROS represents a milestone. Ongoing European multicenter trials further support the efficacy of sirolimus in pediatric and adult patients with complicated malformations.Targeting arteriovenous malformations with MEK inhibitors (e.g., trametinib) has shown promising early results in multicenter phase II trials, with clinical benefit but relevant cutaneous toxicities. Targeted therapy has moved from experimental to clinical application in CVM. Genetic testing is essential for treatment selection, while multidisciplinary management remains crucial to balance efficacy and safety. Future perspectives include combination strategies with interventional or surgical approaches to optimize long-term outcomes. • Updated Classification of Vascular Anomalies. Journal of Vascular Anomalies June 2025, Volume 6, Number 2 • Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN VASCA. Orphanet Journal of Rare Diseases (2024) 19:213 • Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations. JCI Insight. 2023;8(21) • Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS). Genetics in Medicine (2023) 25, 100969 • Trametinib treatment for early-stage malformations: A multicenter, prospective, single-arm pilot study. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2025.07.033.