This chapter begins by outlining the regulatory requirements and development stages that apply to certified reference materials (CRM) in toxin production. The intended use of CRMs becomes an important factor for properly using the certified values and providing reliable analytical data. The chemical nature of marine and freshwater biotoxins and their physical properties allow the classification of the marine natural products into several families of lipophilic and hydrophilic toxins. Cylindrospermopsins, nodularins, microcystins, and anatoxins are identified mostly as cyanobacterial freshwater toxins. Marine toxins and freshwater CRMs play a decisive role in the validation of testing methods that are applied within the framework of quality assurance in routine analytical measurements through a reference measurement system, and the highest level of accuracy and precision is ensured. CRMs are useful to implement the concept of traceability of measurement results in chemistry, biology, physics, and other sciences dealing with materials and/or samples.