Organoids are microtissues that recapitulate the complex structural organization and functions of tissues and organs. Nanoparticles have several specific properties that must be considered when replacing animal models with in vitro studies, such as the formation of a protein corona, accumulation, ability to overcome tissue barriers, and different severities of toxic effects in different cell types. An increase in the number of articles on toxicology research using organoid models is related to an increase in publications on organoids in general but is not related to toxicology-based publications. We demonstrate how the quantitative assessment of toxic changes in the structure of organoids and the state of their cell collections provide more valuable results for toxicological research and provide examples of research methods. The impact of the tested materials on organoids and their differences are also discussed. In conclusion, we highlight the main challenges, the solution of which will allow researchers to approach the replacement of in vivo research with in vitro research: biobanking and standardization of the structural characterization of organoids, and the development of effective screening imaging techniques for 3D organoid cell organization.