Aminoglycosides have been a mainstay in antibacterial therapy for over 50 years. Worldwide today, they are the most commonly used antibiotics because of high efficacy and low cost. However, nephrotoxicity and ototoxicity are two major side effects. Prevention of these side effects has been attempted for several decades, but no clinical treatment has yet been realized. A therapeutic approach based on a novel hypothesis of the toxic mechanism of aminoglycosides is proposed. Aminoglycosides chelate iron, and the resulting iron-aminoglycoside complex is redox-active, catalyzing the formation of free radicals. The prevention of ototoxicity with antioxidants and iron chelators has been successfully demonstrated in guinea pigs. Both hearing loss and vestibular dysfunction induced by several aminoglycosides were significantly attenuated without compromising the antibacterial efficacy of the drugs. This finding may lead to a safe and effective way to eliminate the threat of ototoxicity of this commonly used class of antibiotics.