Aminoglycoside antibiotics maintain a leading role in antibacterial therapy of severe gram-negative infections despite nephrotoxicity complicating 10% to 20% of therapeutic courses. Risk factors for aminoglycoside-induced renal injury have been identified. A variety of maneuvers to protect renal function and minimize toxicity have been suggested, but few have been accepted for clinical use. Aminoglycosides are eliminated by glomerular filtration, but a fraction is reabsorbed in the proximal tubule. Polycationic aminoglycosides bind to anionic, brush-border, phospholipid membranes and are transported intracellularly. Disruption of normal phospholipid trafficking within the cell is evidenced by the presence of myeloid bodies, electron-dense concretions of phospholipid material. Although consistent with aminoglycoside injury, such biochemical and histological changes are observed with other drug exposures in which renal failure does not occur. Therapeutic drug monitoring services have failed to reduce aminoglycoside toxicity over the years, although two pharmacological parameters are imperative. The first is that peak aminoglycoside levels correlate with efficacy, as these agents display concentration-dependent bacterial killing. Second, trough levels reflect nephrotoxicity; the kidney is unable to excrete the dose of aminoglycoside within the dosing interval owing to impaired function. These two points have led to numerous reports evaluating once-daily dosing of aminoglycosides in which the cumulative dose for a 24-hour period would be administered as a single dose. This would take advantage of concentration-dependent "bug" killing as well as the post-antibiotic effect while minimizing repeated exposure and potential nephrotoxicity. Further trials are warranted to establish specific guidelines for once-daily as well as every 36- to 48-hour dosing regimens in patients with established renal impairment for specific organisms and specific types of infection.