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The development of a multi-mycotoxins method using LC-MS/MS is necessary and it is clear that the development of such method involves many compromises in the choice of the different parameters. This review summarizes applications using conventional experimental designs and some recent studies using response surface methodology (RSM) as a mathematical modeling tool for the optimization of extraction procedures. The authors also discuss pros and cons of the different procedures. To our knowledge, it is the first review on experimental desi