In order to provide personalized patient treatment, a large number of analytical procedures is needed to measure a large variety of drugs in various human matrices. The analytical technique used for this research is Liquid Chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS). Each patient setting may require a specific matrix. Sweat and hair samples may be used to monitor drug abuse. Therapeutic drug monitoring (TDM) performed with the use of blood and plasma samples may be suitable for in-patients, while dried blood spot (DBS) may be more suitable for outpatients. These alternative matrices make sampling less invasive. In addition, DBS reduces patient travelling time, because sampling can be performed at home. This provides more cost-efficient patient care. The use of DBS is very promising, but the investigated parameters showed not to be underestimated and need to be considered before performing patient analysis. In the near future, personalized patient treatment will not only comprehend personalized dosing of patients, but also a personalized choice of matrix which best suits the patients’ circumstances and optimal needs. In summary we can say that the used sample matrix affects the method development and analytical performance with LC-MS / MS. The influence of the matrix can result in altered stability of the substance, formation of complexes with other substances or binding of the substance with the sampling material. More insight in these matrix effects will lead to improved analytical methods and performance, but will above all improve patient care and research.