It is often suggested that there are substantial anatomic barriers to the passage of antibiotics from the circulation into tissues and fluids of the body. In fact, most capillary beds are fenestrated and allow the passage of antimicrobial agents into tissue fluids fairly readily. At equilibrium, the mean concentrations of free (unbound) antibiotic in plasma and tissue fluids over the dosing interval are equal. However, the time to achieve equilibrium may range from minutes to days, depending on the ratio of surface area to volume of the tissue fluid compartment. There are several sites in the body in which nonfenestrated capillary beds pose appreciable barriers to the diffusion of antibiotics, namely the central nervous system, the eye and the prostate gland. Only lipid-soluble drugs traverse these capillaries readily. If the nonporosity of the capillaries were the only barrier to drug diffusion in these sites, the mean concentrations would eventually be equal to those in the plasma. However, in the central nervous system and the retina of the eye, transport pumps for organic anions combine with the effect of nonporous capillaries to produce concentrations which, even at equilibrium, are lower than those in the plasma. Bulk flow may also play a role in lowering drug concentrations in the cerebrospinal fluid. In the prostate gland, pH partition may cause mean concentrations in the prostatic secretions to differ from those in the plasma at equilibrium.