The search for protection from aminoglycoside ototoxicity is nearly as old as their use as antibiotics. However, only in recent years has focused research on the mechanisms underlying the insults to the inner ear led to coherent attempts at protection, such as antioxidant therapy or interference with cell death signaling pathways. Successful translation of these therapies from research to the clinic requires consideration of many points: that the protectant have appropriate pharmacokinetics (i.e., be at the right place at the right time), that it not have side effects of its own, and that it not interfere with the efficacy of the aminoglycosides as antibiotics. Encouraging progress has been made to bring us closer to the goal of preserving the benefits of aminoglycosides and eliminating their deleterious side effects.