The risk associated with the consumption of Shellfish has leaded the authorities worldwide to install monitoring systems that prevent toxic Shellfish from reaching the markets and intoxicate the consumers. The mousse bioassay (MBA) has been considered as the reference monitoring method for marine toxins. The MBA for lipophilic toxins was developed by Yasumoto and has been used until as a universal detection method for lipophilic compounds. For a routine monitoring control, experts on biotoxins consider that it is not practical to fully determine the presence of all toxin levels in the mollusks. The liquid chromatography coupled to mass spectrometry (MS)/MS technique has been used for many years for the detection of lipophilic marine toxins in different molluscan Shellfish matrices such as mussel, clams, or cockles. In Europe, chromatographic techniques coupled to mass spectrometry were the method of choice to replace the MBA to detect lipophilic marine toxins.