Substances can be eliminated from the brain parenchyma either by metabolism or efflux. This review considers efflux, which can occur via perivascular routes or via the blood–brain barrier. The quantitative importance of these different mechanisms is assessed using clearance defined as the rate of elimination of the substance from interstitial fluid (ISF) divided by its ISF concentration (see Appendix A). If the rate of elimination and the concentration can both be measured, the clearance is calculated using this definition. Often, however, it is calculated from the half-life and volume of distribution of the substance as explained in Appendix A. The total clearance of a substance is the sum of its clearances by all mechanisms.