The establishment of a quality system and conformation to Good Laboratory Practices (GLP) and/or ISO guidelines is important for both industries and regulatory agencies. For an analytical laboratory, the best way to ensure quality of results is to use validated methods backed up with appropriate certified reference materials (CRMs). The latter include calibration solution CRMs, which are essential for accurate instrument calibration, and sample matrix CRMs, which are important for verifying the complete analytical method from extraction to data analysis. Unfortunately, one of the greatest impediments to analytical work in the natural products field has been the lack of accurate calibration standards and reference materials. Since 1987, the Certified Reference Materials Program at the National Research Council’s Institute for Marine Biosciences has been producing certified calibration standards and matrix reference materials for a wide range of marine and freshwater algal biotoxins. This presentation will give an overview of the research that goes into the development of CRMs, particularly those intended for accurate calibration of analytical methods. A number of key steps in the production of CRMs will be discussed, namely, stability testing and accurate quantitation. Stability testing is essential for understanding both shipping and long-term storage conditions. Quantitation of CRMs involves a cross-comparison of results from different procedures, including gravimetry, liquid chromatography, and capillary electrophoresis coupled with diverse detection systems (UVD, CLND, FLD, MS), and quantitative nuclear magnetic resonance.