Immune responses following either natural or experimental rotavirus infection provide protection against subsequent rotavirus illnesses, and the mechanisms involved have been examined in humans and animals. In adult volunteers challenged with human rotaviruses, protection has been shown to correlate with serum and intestinal antibodies; however, titers of no specific antibody could be used reliably as a marker of protection, including neutralizing antibody to the challenge virus. Studies in children confirmed these general associations between antibody titers and protection, but the serotype specificity of antibody and its role in protection remained unclear. Studies in mice suggested antibody, CD8 cells, and a third, undetermined, factor as mediators of protection. Antibody appeared to be most important, both in resolution of infection and protection against subsequent infection, but its activity was not serotype specific. CD8 cells helped resolve rotavirus infection but were less important in protection against reinfection. The third factor remains to be identified.