Currently, no approved medicines are available for the prevention or treatment of hearing loss. Pharmaceutical industry productivity across all therapeutic indications has historically been disappointing, with a 90% chance of failure in delivering a marketed drug after entering clinical evaluation. To address these failings, initiatives have been applied in the three cornerstones of medicine discovery: target selection, clinical candidate selection, and clinical studies. These changes aimed to enable data-informed decisions on the translation of preclinical observations into a safe, clinically effective medicine by ensuring the best biological target is selected, the most appropriate chemical entity is advanced, and that the clinical studies enroll the correct patients. The specific underlying pathologies need to be known to allow appropriate patient selection, so improved diagnostics are required, as are methodologies for measuring in the inner ear target engagement, drug delivery and pharmacokinetics. The different therapeutic strategies of protecting hearing or preventing hearing loss versus restoring hearing are reviewed along with potential treatments for tinnitus. Examples of current investigational drugs are discussed to highlight key challenges in drug discovery and the learnings being applied to improve the probability of success of launching a marketed medicine.