Traditionally, antibiotics have been administered intravenously (IV) for serious systemic infections. As more potent oral antibiotics were introduced, and their pharmacokinetic aspects studied, orally administered antibiotics have been increasingly used for serious systemic infections. Antibiotics ideal for oral administration are those that have the appropriate spectrum, high degree of activity against the presumed or known pathogen, and have good bioavailability. Oral antibiotics with high bioavailability, that is > or = 90% absorbed, achieve serum/tissue concentrations comparable to IV administered antibiotics at the same dose. The popularity of "IV to PO switch therapy" is possible because of the availability of many potent oral antibiotics with high bioavailability. Initial IV therapy is appropriate in patients who are in shock/have impaired intestinal absorption, but after clinical defervescence, completion of therapy should be accomplished with oral antibiotics. As experience with "IV to PO switch therapy" has accumulated, confidence in oral antimicrobics for therapy of serious systemic infections has continued to increase. The trend in treating serious systemic infections entirely with oral antimicrobial therapy will continue, and is clearly the wave of the future.