The influence of inoculum size on severity of disease for those organisms which multiply in the host is uncertain and not often addressed: the infecting dose is not known in natural situations. Experimental studies, where the dose is known, arc discussed, as well as different natural situations in which the relative dose can be inferred. The advantages and drawbacks of the various methods are debated. The following sections focus on two infections: salmonellae and malaria. For salmonellae, natural infections are compared using indirect markers of dose: incubation period, attack rate and type of vehicle. No evidence of a dose-severity relationship is found for typhoid, whereas there is some evidence for such a relationship for the food-poisoning salmonellae. Analysis of typhoid volunteer data suggests a dose-severity relationship; the critical role of illness definition in determining the findings is discussed. Malaria therapy for neurosyphilis provides a unique source of information on large numbers of human subjects in whom a disease was induced artificially. An extensive review of the malaria literature provides no conclusive evidence on the relationship between dose and severity. The original records for patients from the Horton hospital in Epsom are analysed. Among 589 non- immune patients receiving vivax and 81 receiving ovale, who were not treated within the first 5 days, no consistent relationships are found between any direct measure of dose (mosquito number, sporozoite number, or trophozoite number) and any measure of severity including peak fever and parasitaemia levels. Dose is inversely proportional to prepatent period, and patients with longer prepatent periods are more likely to have tertian fever, undergo spontaneous recovery and not to get modifying treatment The implications of these findings for the pathogenesis of malaria and for natural malaria are discussed. The final section explores more general issues of the relationship between dose and pathogenesis.