The global incidence of HCC is rising; in the United States, its rise is in parallel to that of cirrhosis due to the HCV and obesity epidemics. The lack of adequate treatment for advanced HCC mandates both prevention and early detection of these lesions. The limitations of currently available histopathologic evaluations, serologic markers, and radiographic imaging modalities in detecting HCC and its precursors have been outlined in this review. Refinements of all of these may lead to better HCC detection, earlier intervention, and successful treatment. Randomized controlled trials are necessary to evaluate the most efficacious and cost-effective approach to screening.