Accumulation of marine toxins in seafood displays several threats on food safety and public health around the world. Moreover, these accumulated toxins can reach toxic levels affecting not only humans but also poisoning or even killing marine organisms. Furthermore, threats become more complicated by the fact that most of the marine organisms are able to metabolize these toxins after absorption, yielding other potentially toxic compounds. So far, more than 200 lipophilic marine toxins have been reported worldwide. The situation is further complicated by the fact that seafood like shellfish may be contaminated by toxins from different toxin groups, and the effect of one class of compound on the absorption, distribution, metabolization and excretion of another class must be considered in determining the potential overall toxicity. These findings have raised several questions about targeted detection of toxins, and methods used due to their dependence on standard reference solutions. In this context, in-depth investigation on detection and profiling during accumulation and metabolization of lipophilic marine toxins is presented in this doctoral thesis. To this end, a metabolomics framework was established, which was mainly founded on the screening possibilities of HRMS analytical instrumentation. Then, the developed methodology was applied to study the local toxin status in the Belgian part of the North Sea (BPNS).