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Recently, so-called third generation sequencing methods, including Next Generation Sequencing (NGS) with error correction (ecNGS), have emerged, pushing the limits of these technologies even further in terms of sensitivity, with an extremely low technical error rate. From an experimental point of view, these new technologies make it possible to directly assess the mutations induced by a substance on the native DNA of test organisms in vitro and/or in vivo, with extremely high accuracy and in multiple genomic regions. This makes it possible to highlight extremely rare mutations. A roadmap describing the stages that could ultimately enable the regulatory adoption of ecNGS to determine mutagenic and carcinogenic potential has recently been proposed. From a clinical point of view, these techniques could facilitate the early detection of cancers by enabling the identification of mutated DNA molecules in biological samples, thus providing clinicians with a tool to help identify and manage cases of cancer. Finally, the contribution ecNGS makes to characterizing “mutational signatures” could contribute toward determining the etiology of a cancerogenesis process, identifying carcinogens at the origin of tumors, finding new opportunities to prevent cancer, developing specific therapies, and adjusting (or changing) treatment. These technologies require powerful, non-harmonized bioinformatics processes which are currently expensive and not widely available. However, their scope of application is so broad and promising for the main research areas as well as for non-clinical developments that their gradual implementation seems inevitable.