Therapeutic EUS has witnessed exponential growth in the last decade, but it has been considered investigational until recently. An increasing body of good-quality evidence is now demonstrating clear advantages over established alternatives, adding therapeutic EUS to management algorithms of complex hepato-pancreato-biliary (HPB) and gastrointestinal (GI) conditions. In this review, the available evidence and clinical role of therapeutic EUS in established and evolving applications will be discussed. A Graphical Summary for each scenario will provide (1) technical steps, (2) anatomical sketch, (3) best-supporting evidence, and (4) role in changing current and future GI practice. Therapeutic EUS has accepted well-established applications such as drainage of symptomatic peripancreatic fluid collections, biliary drainage in failed endoscopic retrograde cholangiopancreatography, and treatment of acute cholecystitis in unfit-for-surgery patients. In addition, good-quality evidence on several emerging indications (e.g., treatment of gastric outlet obstruction, local ablation of pancreatic solid lesions, etc.) is promising. Specific emphasis will be given to how these technical innovations have changed management paradigms and algorithms and expanded the possibilities of gastroenterologists to provide therapeutic solutions to old and emerging clinical needs. Therapeutic EUS is cementing its role in everyday practice, radically changing the treatment of different HPB diseases and other conditions (e.g., GI obstruction). The development of dedicated accessories and increased training opportunities will expand the ability of gastroenterologists to deliver highly effective yet minimally invasive therapies, potentially translating into a better quality of life, especially for oncological and fragile patients.