Drug ototoxicity research has relied traditionally on animal models for the discovery and development of therapeutic interventions. More than 50 years of research, however, has delivered few--if any--successful clinical strategies for preventing or ameliorating the ototoxic effects of common pharmacological drugs such as aminoglycoside antibiotics. One of the reasons for this lack of success is that results obtained on animal models frequently cannot be correlated with the responses of human beings. The low levels of human predictability with standard animal ototoxicity tests are associated, in turn, with the fact that the cellular and molecular mechanisms activated by ototoxic drugs are largely unknown. Thus, agents that for unknown reasons and by an unknown mechanism were able to somewhat prevent or ameliorate drug ototoxicity in an animal model generally fail--for unknown reasons--to show similar properties in a clinical trial. The incorporation of high-throughput screening (HTS) models and methods to the arsenal of techniques available to hearing researchers may modify this situation by helping to elucidate the mechanisms of drug toxicity. This knowledge will be crucial in designing acute experiments to be performed on animal models, aimed at identifying effective strategies for the prevention of drug ototoxicity in humans.