Vascular malformations (VMs) are described as congenital malformations of the vasculature derived from capillaries, veins, lymphatic vessels, arteries, or a combination of these vessels. They can cause significant morbidity resulting from soft tissue hypertrophy, bony abnormalities, and even organ compromise. They are usually treated with various interventional procedures to achieve local control; however, the chance of success decreases as the anatomical distribution of the malformation widens. Unfortunately, medical treatment options have been quite limited in these patients. Also, infantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regresses satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. Sirolimus, a mammalian target of Rapamycin (mTOR) inhibitor, is an antiangiogenetic and antiproliferative pharmacologic agent that has been used for the management of VM in the last decade. Mammalian target of rapamycin seems to play a key role in the signal pathway of angiogenesis and subsequently in the development of vascular anomalies. Recently, the successful use of sirolimus has been reported in children with lymphatic malformation, IHs, PHACE syndrome, and Kasabach-Merritt phenomenon followed by kaposiform hemangioendothelioma or tufted angioma. Sirolimus is a safe and effective medical treatment for widely distributed VMs with significant lymphatic components and no further local treatment option.