Screening programs for patients with cirrhosis are designed to detect hepatocellular carcinoma at an early stage when effective treatment is feasible and may provide long-term survival benefits. However, only a minority of these patients will be considered candidates for liver transplantation or surgical resection and hence, most cases will be evaluated for other medical options. While systemic therapy has never been shown to bear a relevant antitumoral activity with an impact on survival, there are several locoregional options that can achieve a high rate of objective responses (this includes complete necrosis or partial reduction in tumor burden). Percutaneous ablation by any of the available methods (ethanol injection, radiofrequency, microwave, acetic acid injection, laser) is extremely useful in patients with small solitary tumors. Results indicate that 90% of tumors < 2 cm will be completely ablated using the percutaneous approach. However, when tumor size exceeds 3 cm and/or the number of nodules is greater than 3, the rate of treatment success is significantly reduced. In patients with large/multifocal disease, the sole option that has been shown to provide treatment efficacy with moderate improvement in survival is chemoembolization. New therapeutic agents should target biological mechanisms in a tailored strategy, and the demonstration of beneficial results for patients should be obtained by large, randomized, controlled trials comparing active intervention versus no treatment.