Repeated infections with the ‘mucosal’ pathogen rotavirus are common in children. Subsequent rotavirus infections usually cause milder symptoms than first‐time infections. Therefore, although natural rotavirus infection attenuates the severity of subsequent infections, it does not prevent reinfection or mild disease. On the other hand, natural infection with ‘systemic’ viruses such as measles, mumps, rubella, or varicella often confers life‐long protection against mild disease associated with reinfection. The degree to which differences in the pathogenesis of systemic and mucosal pathogens determines differences in the capacity of natural infection to induce life‐long protective immunity will be discussed. This paradigm will be used to explore the immunological effector functions associated with protection against rotavirus challenge.