The theoretical basis of the intravenous isotope method has been examined with particular emphasis on the physiological significance of the area of the curves obtained and the meaning of the peak activity. It is concluded that the area is proportional to the volume of distribution of the indicator within the monitored volume, and inversely related to the cardiac output. The peak activity will be a measure of the fractional blood flow to the brain. It will be affected, however by the extension of the input bolus to the brain but also by the transit time within the brain itself. An unexpected low cardiac output, for instance, will lead to an over-estimation of the cerebral blood flow as derived from the peak activity even though the concomitant prolongation of the input bolus will reduce the error. The theory thus suggests that central circulatory variables will have an influence on the curves obtained and thus also will influence the validity of the method. The validity can be substantially improved by (1) the determination of the input bolus by, for instance, a gamma detector focused over the aortic arch, and (2) by the determination of the cardiac output; this can theoretically be carried out if a true intravascular indicator is used and the investigation is expanded to include the determination of the systemic blood volume.