Monitoring and management programs for marine toxins in seafood depend on efficient detection tools for their success in protecting public health. Here we review current methods of detection for neurotoxic shellfish poisoning (NSP) toxins, and current knowledge in brevetoxin metabolism in shellfish. In addition, we discuss a novel approach to developing monitoring tools for NSP toxins in molluscan shellfish. NSP is a seafood-borne disease caused by the consumption of brevetoxin-contaminated shellfish. Brevetoxins are a suite of cyclic polyether compounds found in blooms of the marine dinoflagellate Karenia brevis (K. brevis) and are potent neurotoxins. Preventive controls for NSP in the U.S. currently rely upon environmental monitoring of K. brevis blooms and assessment of their shellfish toxicity by mouse bioassay. The mouse bioassay for NSP approved by National Shellfish Sanitation Program was developed in the 1960s when very little information on the structural and toxicological properties of brevetoxins in algae and shellfish was available. Alternative methods to mouse bioassay based on current scientific knowledge in the area are needed for monitoring NSP toxins. It is now established that brevetoxins are metabolized extensively in shellfish. Algal brevetoxins undergo oxidation and reduction, as well as conjugation with fatty acids and amino acids in shellfish. Recently, three metabolites have been identified as biomarkers of brevetoxin exposure and toxicity in Eastern oyster (Crassostrea virginica) and hard clam (Mercenaria sp.). The role of these biomarkers in monitoring NSP toxins in K. brevis exposed molluscan shellfish is reviewed. Comparisons of biomarker levels by liquid chromatography-mass spectrometry (LC-MS) with composite toxin as measured by enzyme linked immunosorbent assay (ELISA), and shellfish toxicity by mouse bioassay, support the application of these biomarkers as a dynamic and powerful approach for monitoring brevetoxins in shellfish and prevention of NSP.