Treatment of chronic hepatitis B and C viruses (HBV and HCV) is still disappointing, and both are the major causes of liver cirrhosis and hepatocarcinoma. Interferon and lamivudine are the registered drugs for chronic HBV but are scarcely effective on HBeAg-negative patients, and resistance due to virus mutation is the rule with lamivudine. Interferon and ribavirine represent the standard treatment for chronic HCV but less than the half of the infected population is eligible for this treatment and less of the half of treated patients will experience a sustained response. No single new drug to date has shown the potential to overcome this dismal picture. Combined strategies are thus the currently most available approach to improve the response rate of chronic HBV and HCV infection, with a subsequent decrease in the number of patients developing hepatocellular carcinoma (HCC). Combination of thymosin alpha 1 with interferon or antiviral agents is currently the most promising option, but nontoxic immunomodulants, such as oral MIMP, should be explored. This review focuses on the difficulties with current therapy and the rationale for use of combination therapy with thymosin alpha 1 for both HBV and HCV therapies.