Mediastinal and abdominal vessels have historically served as landmarks to guide routine diagnostic and therapeutic EUS procedures. Major vascular structures including the heart, aorta, celiac axis, portal vein, hepatic veins, mesenteric vessels, and aberrant vascular shunts such as spleno-renal shunts associated with portal hypertension are easily identified. Even smaller vascular structures such as the gastro-duodenal artery, splenic vessels, hepatic artery and portal vein branches can be confidently identified and traced. Vascular access and therapy are now emerging as new targets for EUS-guided interventions. This chapter reviews the current clinical literature regarding EUS-guided vascular interventions, including management of nonvariceal and variceal GI bleeding, EUS-guided portal vein access and therapeutic implications, and EUS-guided cardiac access and therapy.