Method development for diagnostic liquid-chromatography–tandem mass spectrometry (LC-MS/MS) assays are not broadly discussed in publications. Certain aspects of the development process are thus learned via experience. This article touches on a number of aspects that should be contemplated during method development for LC-MS/MS tests beyond sample preparation, chromatographic separation, and mass spectrometric detection. Utilization of factors intrinsic to LC-MS/MS, such as isotopically labeled internal standards and appraisal of transition ratios, engenders confidence in assay development and accelerates movement toward validation and testing.