Recent findings from our laboratory regarding the immune response of mice to rotavirus (a mucosal pathogen) show that although in most situations an acquired (T or B cell or both) response is necessary for elimination of primary rotavirus infection, unidentified innate mechanisms can also play a role in some mouse strains. Similar to what is seen with many other viruses, CD8+ T cells appear to provide the first but not the exclusive mechanism that mediates clearance of a primary rotavirus infection. Antibodies are the critical mediators of prevention against rotavirus reinfection. Nonneutralizing IgA monoclonal antibodies directed against VP6 (an internal structural rotavirus protein) can mediate immunity against rotaviruses in vivo. Rotavirus-specific CD8+ T cells can mediate their antiviral effect in the absence of perforin, fas, or interferon-gamma and are preferentially represented in the subset that expresses high levels of the enteric mucosal homing receptor alpha4beta7.