Two major classes of drugs currently in clinical use can cause permanent hearing loss. Aminoglycoside antibiotics have a major role in the treatment of life-threatening infections and platinum-based chemotherapeutic agents are highly effective in the treatment of malignant disease. Both damage the hair cells of the inner ear, resulting in functional deficits. The mechanisms underlying these troublesome side effects are thought to involve the production of reactive oxygen species in the cochlea, which can trigger cell-death pathways. One strategy to protect the inner ear from ototoxicity is the administration of antioxidant drugs to provide upstream protection and block the activation of cell-death sequences. Downstream prevention involves the interruption of the cell-death cascade that has already been activated, to prevent apoptosis. Challenges and opportunities exist for appropriate drug delivery to the inner ear and for avoiding interference with the therapeutic efficacy of both categories of ototoxic drugs.