Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and do not interfere with its antitumoral activity. Many therapies have been successful in preclinical work, but only a few have shown any protection in the clinic, and none have been approved by the FDA. This review summarizes the clinical and preclinical studies of the most effective small-molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field.