Treatment decisions for hepatocellular carcinoma involve the evaluation of multiple factors including tumor size, location, and morphology; comorbidity and/or extrahepatic disease; health status; patient preferences; and the treating physician's expertise and skill. For patients who are not candidates for transplant or resection, and for whom other therapies (radiofrequency ablation, systemic chemotherapies, transarterial embolization or chemoembolization), may have limited efficacy, an urgent need for bridging procedures, to enable surgery or ablation, or meet transplantation criteria, has led to investigations with radioembolization. A number of recent reports have supported the effectiveness of Yttrium-90 ((90)Y) labeled microspheres to treat intermediate and advanced disease in patients with good overall functional status and liver reserve; patients with portal vein involvement and in a limited role to treat unresectable early-stage disease. This review addresses response rates and survival benefit following radioembolization in different patient populations, in centers throughout Europe, North America, and Asia, and across the spectrum of patients presenting with various prognostic factors. By using stringent selection criteria and conservative models for calculating radiation dosage, radioembolization can be performed safely even in cirrhotic patients, without postembolization syndrome or radiation-induced liver disease, and even with multiple treatments to whole or part of the liver.