The combination of gas chromatography and mass spectrometry (GC/MS) is generally recognized as offering the best sensitivity and specificity for the detection and measurement of drugs and their metabolites in biological specimens. This finding has resulted in the widespread use of GC/MS in many areas of pharmacology and toxicology. However, a GC/MS assay can be performed in many ways, depending upon the specific requirements of the analytical tasks. For example, pharmacokinetic studies generally employ chemical ionization and single-ion monitoring to obtain optimum sensitivity, whereas GC/MS methods for confirmation of the presence of drugs of abuse in urine most often use electron ionization and multiple-ion monitoring to obtain conclusive results. Another example is the increasing use of the combination of gas chromatography and tandem mass spectrometry (GC/MS/MS) for analyses requiring sensitivities better than nanograms per milliliter. Examples of the application of GC/MS and GC/MS/MS methods for the detection of Δ9-tetrahydrocannabinol, naltrexone, and their active metabolites are described and compared in terms of sensitivity, specificity, and unique features.