1. Experimental determinations of blood-brain barrier permeability from measurements of uptake of tracers by brain are limited in two ways. First, there are experimental limitations that are specific to the particular method being used. These limitations include the range of permeability values that a particular method can reliably determine (sensitivity); whether repeated experiments are possible in the same animal; whether regional values can be determined; and to what degree the chemical composition of the perfusate passing through the brain can be controlled. 2. A second set of limitations on permeability determinations is of a more general, physiological nature. These constraints apply to a greater or lesser degree to all experimental determinations, and may limit the accuracy and reliability of the permeability values obtained; although certain reliable upper and lower bounds can be determined. These general factors include: capillary heterogeneity (i.e. variations in capillary lengths, surface areas, blood flows, etc.); the possibility of binding to circulating plasma proteins, especially albumin; and the possibility of capillary recruitment and de-recruitment with changes in cerebral blood flow.