Rotaviruses (RVs) are important human pathogens. The murine model of RV infection has been very useful in clarifying the mechanisms that mediate clearance of primary RV infection, and the mechanisms that mediate immunity to reinfection. The use of immunodeficient strains of mice, immunodepletion studies with specific monoclonal antibodies (MAbs), and passive transfer of purified cells are three basic, complementary experimental approaches that have been used for this purpose, and are the subject of this chapter. These experimental approaches analyze the outcome of RV infection under artificial conditions; thus, the relevance of the results obtained, to the physiological immune response of immunocompetent mice or humans, is at times difficult to establish. For example, immunodeficient strains of mice frequently develop compensatory immune mechanisms that are potentially absent or nonfunctional in immunocompetent mice. Immunodepletion experiments introduce into the experimental animal high (nonphysiological) levels of antibodies (Abs) that potentially have other immunomodulatory effects different from the desired one, and, many times, depletion strategies fail to completely eliminate the target cell population. Passive cell transfer experiments analyze the antiviral capacity of a specific cell population (many times abnormal in number), independent of other cells with which it may normally interact, and in an environment to which it is at least partially alien. Because of these and other limitations of such experimental approaches, one should be very careful in selecting adequate controls, and cautious in the interpretation of the results, by taking into account results obtained with two or three of the approaches and analysis of the characteristics of the immune response in normal animals. The combination of two or three strategies (for example, passive cell transfer into immunodeficient hosts and immunodepletion of selected cell populations in immunocompetent hosts) have proven particularly useful in the study of immunity to RV.