1. Genetic differences between virus strains give rise to characteristic sharp differences in virulence, in lag period, in tissue predilection, in host and tissue affinity, and in the disease syndrome. 2. Genetic differences between host animals of the same species determine whether — and the extent to which — an infecting virus propagates, how long the incubation period lasts, in what tissue early virus multiplication electively takes place, and whether the animal becomes clinically ill and succumbs to specific disease or not. 3. Differences in the route of inoculation can determine whether, and to what extent virus multiplies, how long the incubation period or lag phase lasts, in what tissues early multiplication takes place, and what kind of clinical response results. 4. Effective selection for adaptation in a constant host necessarily results in also changing the genetically determined tissue-preference pattern of a virus strain. The extent of change will depend on the power, duration and rigidity of selection, and on the genetic limitations of the virus. 5. FMD virus strains that have not been specially adapted in adult mice show no predilection for muscle of the hind limbs, irrespective of the route of inoculation. The only consistent evidence of predilection for multiplication in muscle of the hind limbs was obtained in the case of a preadapted strain (RV11mo) inoculated into muscle tissue of the mouse strain to which it had been adapted. 6. After i. p. inoculation the earliest evidence of active virus multiplication, and subsequently also the highest virus concentration, is found in the pancreas. Thus ability to multiply in pancreatic tissue of adult mice may well be a property of most strains of FMD virus irrespective of the degree of their adaptation to growth in other tissues. High virus concentrations in the pancreas are frequently correlated with severe oedema of this tissue. 7. Where virus multiplies preferentially in the pancreas or in uninvestigated tissues, clinical signs observed were those of general malaise without paralysis, while preferential propagation in muscle usually first resulted in paralysis of the hind limbs.