alpha-Galactosylceramide is a glycolipid derived from marine sponges that is currently in human clinical trials as an anticancer agent. It has also been shown to be effective in reducing the amount of hepatitis B virus (HBV) DNA detected in mice that produce HBV constitutively from a transgene. It was assumed that all of the antiviral and antitumor activities associated with alpha-galactosylceramide were mediated through the activation of NK T cells. However, we report here an additional unpredicted activity of alpha-galactosylceramide as a direct antiviral agent and inducer of the innate host defense pathway. To exploit this activity, we have developed a new class of smaller, orally available glycolipids that also induce the innate host defense pathway and have direct activity against HBV and hepatitis C virus.