Generally, there are three important drivers of ncRNA research. First, the 3Rs principle to reduce the number of studies and the number of animals used in the studies (Russell and Burch, 1959) that has been implemented in Directive 2010/63/EU on the protection of animals used for scientific purposes. Second, the motivation to accelerate substance development and the RA process. Third, the incentive to gain knowledge that is of increased biological and toxicological relevance. Accordingly, research on ncRNA should not merely strive to replace apical endpoints by earlier molecular / cellular effects but aim to create a new toxicological paradigm that provides much more comprehensive information. Even though this goal may only be reached in the long term, it is of high scientific relevance since an improved biological understanding of mechanisms of toxicity will serve to improve the RA of substances and products. Therefore research should also address scientific deficiencies of standard toxicity tests and opportunities for ncRNAs to contribute to overcoming such deficiencies (e.g. for specific endpoints, such as non-genotoxic carcinogens and reproductive / transgenerational toxins, including in utero exposure leading to adult diseases). Nevertheless, to begin with, it may be beneficial to include ncRNA profiling, just as other ‘-omics’ technologies, in the control groups used in Good Laboratory Practice-compliant toxicological studies. Such investigations should preferably be conducted as collaborative studies and will enable a prospective comparative assessment of the new tools and the collection of ncRNA data within a regulatory context.