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The interactions between a causative agent and a susceptible host involve a series of responses most of which are subclinical or asymptomatic but a few of which are manifested by clinical illness. The factor(s) which tip the balance are poorly understood in both acute and chronic diseases. It is designated here as the clinical illness promoting factor (CIPF), a third ingredient. Among infected persons some leads have been found as to why clinical illness develops: in tuberculosis genetic susceptibility plays a key role, as shown in twin studies; in EBV infections age at the time of infection, genetic, and psychosocial factors determine both the expression and the severity of illness; in poliomyelitis age, exercise in the incubation period, and genetic background are related to the development of paralysis. In the relationship between viruses and cancer, viruses and chronic diseases, or inanimate pathogens like tobacco and lung cancer, we know very little as to the factors that result in clinical disease among the many who are presumably susceptible and fully exposed. Epidemiologic study is urged to identify this CIPF or "third ingredient."