The factors that affect the presence and duration of the post-antibiotic effect (PAE) for different antimicrobial agents are described, and the clinical importance of the PAE is discussed. Proposed mechanisms by which the PAE occurs include both nonlethal damage induced by the antimicrobial agent and a limited persistence of the antimicrobial agent at the bacterial binding site. The specific microorganism-antimicrobial combination is the most important factor to influence the presence and duration of the PAE. Additional factors are antimicrobial combinations and experimental conditions, including the antimicrobial concentration and the length of the antimicrobial exposure. Most antimicrobial agents produce a PAE when tested against gram-positive cocci. However, against gram-negative bacilli, beta-lactam antibiotics (except for imipenem) have a minimal, or even a negative, PAE. Aminoglycosides, inhibitors of protein and nucleic acid synthesis, and fluoroquinolones have PAEs against gram-negative bacteria that range from one to four hours. In vivo PAEs are generally longer than in vitro PAEs for the same microorganism-antimicrobial combination. In human studies, aminoglycosides, which have an extended PAE against gram-negative bacilli, have been effective when given in once-daily dosing regimens that allow serum drug concentrations to fall below the minimum inhibitory concentration. Extending the dosing interval of an antimicrobial agent that has a PAE has several potential advantages, among them reduced cost, less toxicity, and better compliance among outpatients receiving antimicrobial therapy. Although data are limited, animal and human studies provide support for the clinical importance of the PAE. Further research into the impact of the PAE on antimicrobial dosing, efficacy, toxicity, and costs is warranted.