<p>Vascular malformations (VMs) are congenital disorders characterized by structurally abnormal blood and lymphatic vessels. Advances in genetics have revealed that most sporadic VMs result from post-zygotic variants in genes involved in key endothelial signaling pathways, including the phosphoinositide-3-kinase (PI3K) and the mitogen-associated proliferation kinase (MAPK) pathways. As these variants are shared with cancer, genetics now have theragnostic impact by helping predict relevant targeted therapies. mTOR and PI3Kα inhibitors such as sirolimus and alpelisib have shown promising efficacy in slow-flow VMs, while reports have suggested that MAPK inhibitors such as trametinib may improve arteriovenous malformations. Despite these advances, several challenges remain, including obtaining accurate genetic diagnosis, enhancing treatment efficacy while mitigating drug-related toxicities, and personalizing multimodal treatment strategies. Emerging approaches such as mutant-selective inhibitors, proteolysis-targeting chimeras, and gene therapy hold promises for improving treatment specificity and minimizing adverse effects. This review provides an overview of the genetic bases of VMs, recent advances in targeted therapies, and future directions in the field, highlighting the ongoing evolution of precision medicine for VMs.</p>