Several clean-up methods are compared for background reduction, analyte recovery, and cost effectiveness in order to successfully analyze a wide variety of multiclass multiresidues in difficult matrices including Chili Powder and Tobacco. The most critical aspects of reliable multiresidue analysis are the reduction of interferences from the sample matrix and analyte recovery. eXtreme|FV®, were compared to an existing ISO accredited QuEChERS method, as well as a dilute and shoot approach are analyzed in conjunction with different filtration techniques for residue analysis by LC-MS/MS for minimal number of steps, speed, reduced reagent use and reduced cost.