Most studies on viral pathogenesis in animals involve small mammals inoculated with pathogens isolated from humans or other large animals. Defective interfering (DI) virus particles remain as intriguing biological entities, the role of which in natural disease is still elusive. Many properties of DI particles are defined in cell culture, uncluttered by the various parameters of host immunologic defenses and clearance mechanisms. The induction of interferon is one of many possible host functions that has been clearly identified to affect the interaction between DI and standard virus. Rabies virus DI particles have been grown in a variety of animal cell cultures and then titrated in animals with very different results. Perhaps the best proof of a role in pathogenesis for DI particles in natural disease is to isolate DI particles directly from infected hosts and to correlate these isolations with avirulence or persistence. Sequential isolates have been obtained from immunosuppressed children with rotavirus diarrhea.