Despite their enormous utility and diffusion, atmospheric pressure ionization mass spectrometry techniques are subjected to relevant drawbacks called matrix effects (ME). These effects could be summarized in matrix-dependent signal suppression or enhancement that could lead to erroneous quantitative results. The most important method parameters as well as linearity, precision, and accuracy could be modified due to interfering compounds present in the matrix. No validation methods could be accepted without a thorough evaluation of ME and possible strategies to minimize or to correct their influence should be addressed. In this article, we investigate mechanisms that lead to ME and discuss calibration techniques and other strategies to limit these phenomena. Significant examples from different fields of application are discussed as well. Sample preparation procedures, together with instrumental improvements and alternative calibration techniques used by many authors, are reported.