Matrix effects are dependent on biological fluid, ionization type, and sample preparation method. Although matrix effects are observed for both ionization types, ESI is especially susceptible, while APCI has proved to be less vulnerable. Sample preparation method has a clear influence on matrix effects as does, in particular, the choice of internal standard. When matrix effects result in severe ion suppression or enhancement of the target analyte by co-eluting residual components, they are typically located in isolated regions of the chromatogram. Postcolumn infusion and postextraction addition methods have been developed for the assessments of matrix effects. Approaches used for eliminating, minimizing, or compensating for matrix effects include improved sample preparation and chromatographic separation, sample dilution, and the utilization of internal standards. Matrix effects may not always be fully circumventable, because a perfectly consistent matrix does not exist, but they can be significantly minimized and largely compensated for by various approaches, such as standard addition, matrix-matches calibration, and the use of isotopic analogs of the analytes as internal standards. (Published Abstract)