Hepatocellular carcinoma (HCC) arises in the context of cirrhosis and chronic hepatitis B virus (HBV) infections, and the diagnosis is often made at advanced stages. Because early-stage diagnosis improves survival, guidelines recommend screening patients at risk for HCC, such as patients with cirrhosis. However, adherence to screening programs is suboptimal. In this review, we discuss the value of HCC screening and provide practical guidance on patient selection and screening methods. International guidelines concordantly recommend HCC screening in patients with cirrhosis, including patients with HBV infections, hepatitis C virus infections with or without sustained virologic response, and nonalcoholic fatty liver disease. There is no consensus on screening patients without cirrhosis, although patients with advanced fibrosis, HBV infections, or nonalcoholic fatty liver disease without cirrhosis have an increased risk for development of HCC. Screening for HCC improves early tumor detection, receipt of curative treatment, and overall survival in at-risk patients. However, potential harms of HCC screening have not been well quantified. Semiannual abdominal ultrasonography is the screening modality of choice. Using ultrasonography in combination with biomarkers, such as α-fetoprotein, may increase accuracy for early HCC detection. The use of magnetic resonance imaging and computed tomography is limited by cost-effectiveness and practical considerations. Increased awareness of HCC screening will allow for earlier diagnosis and potentially curative treatment. We propose a comprehensive screening algorithm for patients at risk for development of HCC, recommending lifelong, semiannual ultrasonography combined with α-fetoprotein testing in patients with cirrhosis and selected patients without cirrhosis.