Critical evaluation of existing data on binding of antibiotics to serum proteins and on pharmacokinetics provides several useful principles for administration of antibiotics. With the exception of the aminoglycosides, antibiotics distribute with total body water, and the concept of a variable apparent volume of distribution leads to incorrect assumptions about restricted extravascular penetration. Antibiotics with a high degree of binding to serum proteins are not necessarily inferior; raising a given drug's binding to serum proteins from 0 to 90% reduces the concentration of free drug in serum and tissue by only one-half. The concentration of an antibiotic in extravascular fluid is essentially constant despite the marked variability of serum levels seen during intermittent administration of the drug. An important factor in determining a successful therapeutic response is maintenance of the level of free antibiotic in extravascular fluid above the minimal inhibitory concentration for the infecting organism. Finally, the extravascular distribution, tissue binding, and free-drug concentration of an antibiotic can be accurately predicted from serum kinetics and serum protein binding.