Several discrete strategies have been suggested to prevent or reduce microbial resistance to antimicrobials, including optimal use of the agents (also known as good stewardship); control, removal, or restriction of antimicrobials; use of antimicrobials in combination; and rotational or cyclic use of antimicrobials. The latter strategy is attractive because it periodically removes from the institutional environment certain classes or specific agents that could induce or select resistance. Hospitalwide studies of aminoglycoside substitution employed from the late 1970s through the early 1990s, although not originally intended to test cycling or rotation of aminoglycosides, serendipitously provided data that may be useful in designing future studies. In particular, one 10-year study at the Minneapolis Veterans' Affairs Medical Center (MVAMC) rotated amikacin and gentamicin use over cycles of 12 to 51 months' duration. Significantly reduced resistance to gentamicin was found when amikacin was used, but resistance to gentamicin returned with the first gentamicin recycle. This was followed by reintroduction of amikacin a second time with decreased resistance to gentamicin and, finally, a second reintroduction of gentamicin without resistance to it recurring. Thus, some evidence of proof of principal can be garnered, albeit subject to considerable criticism. Critical examination of the design of the aminoglycoside rotation study and the unforeseen pitfalls is provided as a 13-element guidance list for design of future rotational studies. Rotational usage practices are likely to be most appropriate for drugs active against gram-negative bacilli because of the wide choices available for rotation. Future availability of new agents active against resistant gram-positive organisms will present the opportunity to cycle these agents as vancomycin substitutes. Careful monitoring of clinical outcomes and resistance will be required. Multicenter controlled trials that follow carefully designed protocols are most likely to produce statistically significant and clinically meaningful results.