The quantification of cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes is important for in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance, which has become an integral part of drug development. The availability of different mass spectrometry-based techniques has revolutionized the scene of quantitative IVIVE. 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. Such selection is a complex matter of balancing cost and benefit for the specific focus of a given project. To date, there has been no systematic comparison of the advantages, limitations, and cost of the available quantitative LC-MS techniques relevant to the measurement of drug-metabolizing enzymes and transporters. 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.