We review recent progress in the discovery and development of small molecule inhibitors against chronic hepatitis B and C infections by listing of the current therapeutic agents and in-depth discussing chemical synthesis and biological results of the recent inhibitor candidates. At present six antiviral drugs have been formally licensed for treatment of chronic HBV infection namely interferon alfa, pegylated interferon alfa-2a and antiviral agents; lamivudine, entecavir, telbivudine and adefovir. Unfortunately, treatment is associated with several side effects and the response rate has been unsatisfactory. β-LPA was recently discovered as a new drug candidate that inhibits viral replication and still in phases II of clinical development. There is an urgent need for the development of novel classes of anti-HBV agents with new molecular structures and optimal pharmacological profiles for the chemotherapy of HBV infection. Although HCV infection can be cured in up to 40% of patients, current treatment is not ideal and is associated with a wide spectrum of side effects and complications. Treatment for HCV has gone through several milestones with the introduction of interferon (IFN) in the early 1990s, the addition of ribavirin in the late 1990s, the pegylation of IFN, and now to the new oral therapies such as BILN 2061, VX-950, JTK-109 and many peptides inhibitors that inhibit viral replication or the translation of viral RNA are in various phases of clinical development. In general, the development of drug-like inhibitors has proven to be a challenging task.