The quantification of drug-metabolizing enzymes and transporters is important for in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance, which has become an integral part of drug development. There are different mass spectrometry-based techniques used for quantitative proteomics, and as more laboratories are opting for the use of these methods, selecting the most appropriate tool is becoming a concern. For the first time, we attempt to determine the significance of cost of different LC-MS methods of quantitative analysis of these proteins and to present a framework to objectively assess the choice of the techniques. Based on our analysis, quantification using labeled internal standards is more expensive per sample but provides higher quality data than label-free quantification. Quantification using absolute quantification synthetic peptides is the approach of choice for analyzing less than nine proteins, whereas when quantifying a defined set of proteins (10-50), such as enzymes, in a reasonably large number of samples (20-100), the quantification concatemer technique is more economical, followed by label-free quantification. When analyzing proteomes or sub-proteomes (≥500 proteins), label-free quantification is more cost-effective than the use of labeled internal standards. A cost-benefit approach is described to assess the choice of the most appropriate mass spectrometry-based approach for the quantification of proteins relevant to IVIVE.