Nitazoxanide, the first thiazolide, was originally developed for the treatment of Cryptosporidium parvum. The antiviral activity of nitazoxanide was discovered by serendipity in patients with AIDS who were treated for cryptosporidial diarrhea and had HBV or HCV co-infection. In preliminary open-label studies of patients with chronic hepatitis B, nitazoxanide suppressed serum HBV DNA and led to loss or seroconversion of hepatitis B e antigen in the majority of patients, as well as hepatitis B surface antigen in approximately a quarter of patients. In Phase II studies of patients with chronic hepatitis C genotype 4, nitazoxanide combined with peginterferon alfa-2a, with or without ribavirin, increased the sustained virologic response rate to 79-80 versus 50% with peginterferon plus ribavirin standard of care. Randomized, controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 and patients with chronic hepatitis B are underway, and new second generation thiazolides are being developed.