This paper reviews intriguing recent findings on the mechanisms of drug induced hearing loss caused by two major classes of therapeutic agents: the aminoglycoside antibiotics and cisplatin. Both drug categories are nephrotoxic as well as ototoxic. Aminoglycosides and cisplatin target the outer hair cells in the basal turn of the cochlea to cause high frequency sensorineural hearing loss in a substantial percentage of patients treated with these drugs. Each group of agents appears to generate reactive oxygen species within the cochlea that trigger downstream mechanisms leading to cell death. Various protective agents including antioxidants show promise in protecting the inner ear from damage in experimental animals. The only successful double-blind, placebo controlled clinical trial using a protective agent to prevent ototoxicity was carried out in China. Aspirin or placebo was given in combination with gentamicin. A significant decrease in hearing loss was observed. Successful clinical implementation of protective agents will require a cautious approach, so that the therapeutic effect of the anti-infective agent or anti-neoplastic drug is not attenuated. This may require novel methods of administration of protective agents, such as injection within the middle ear. This would provide a maximal dose of protective agent without systemic interference with the desired effect of the ototoxic agent.