Oto-toxicity is defined by cochlear and or vestibular cellular lesions due to the use of drugs. The difference in specific mechanisms, the great semi logical variability, the heterogeneity of incriminated drugs, the inaccessibility to bimolecular and histological aspects in the current clinical practice, and the diverse aspects of post-lesional evolution: Are all factors that make it challenging to have systematic diagnostic protocols and systematic consensuses of management. The possibility of replacement with less or non-toxic drugs relies on the peculiar understanding of mechanisms of action in a molecular level. Drugs with the same efficacious action and less or non-toxicity would offer a promising solution for this iatrogenic problem. For now: In most cases, these drugs are indispensable. The idiosyncratic aspect of ototoxicity, the lack of consensus on screening and diagnostic protocols and classification systems, make it difficult to have an unbiased comparability regarding the different populations studied. The pure clinical and audiometric approach is syndromic, it evaluates lesions after their onset, and the classifications that are inspired from them have little specificity, sensibility and prognostic value in early stages. The understanding of the different cellular modalities of inner ear drug-induced lesions related to each specific oto-toxic molecule, would allow: In the one hand: to establish a diagnostic test with high sensibility and specificity before the onset of irreversible cell damage. And in the other hand, would offer new insights into the possibilities of oto-protection, and specific treatment. Oto-toxicity is a fertile field of scientific research which exploration has gained momentum in the last decade; in an experimental point of view, the bimolecular approach seems to be promising: The thorough exploration of inner ear proteome, transcriptome, and genome in physiological and pathological contexts as potential biomarkers of early stages of cell lesions: The clinical application would not only allow a more specific understanding of different mechanisms of iatrogenic oto-toxicity, but also allow new insights into targeted protective and post-lesional therapies.