The unique pharmacokinetic properties of rifampin in humans are discussed in this review. These properties can be better understood by assuming the existence of two pharmacokinetic subsystems; one, the primary subsystem, regulates the time course of the concentration of the antimicrobial agent in the other, the secondary subsystem. The first subsystem includes the intestine and the liver (interconnected through the portal blood and the bile), and the second subsystem includes the tissues, kidneys, and blood of the circulatory system. The connection between the two subsystems in normal conditions is the hepatic veins. The rate of excretion of rifampin in human bile depends, although not exclusively, on its rate of transformation into the biologically active desacetyl derivative. The rate of metabolism increases over the first week(s) of treatment, which results in a corresponding increase of desacetylrifampin excretion in bile. The process is limited and, within a given range of single doses, a transport maximum can be identified. Doses in excess of those associated with the transport maximum generate a more than proportional increase in serum concentrations of the drug. Administration of rifampin causes proliferation of the smooth endoplasmic reticulum of the hepatocyte (probably due to glucuronidation of a fraction of rifampin). This observation explains some of the interactions of rifampin with endogenous and exogenous compounds. The unique distribution of rifampin in human tissues probably results from its capacity to cross biological membranes. Excretion of rifampin in urine does not seem to be associated with any active process.