Advances in the mechanistic knowledge of drug metabolism enzymology are enabling the early-stage understanding of clearance pathways that can be applied in designing clinical pharmacology programs. Clinical drug metabolism studies provide definitive characterization of the metabolic fate of drug candidates. Frequently, the human absorption, distribution, metabolism, and excretion (ADME) study will be the only clinical study of a New Chemical Entity (NCE) designed specifically to characterize metabolism and disposition. In addition to fulfilling a regulatory requirement for registration of a new drug, a main purpose of these studies is to support qualitative extrapolation of the preclinical animal toxicology results to humans by demonstrating that the metabolites formed by humans are formed also by animals. Until recently, clinical drug metabolism studies have been conducted late in the development timeline; however, a changed regulatory environment and improvements in technology are driving the early conduct of human ADME studies. With the current generation of mass spectrometry instrumentation, it is now possible to routinely profile major metabolites in the earliest first-in-human studies without being limited by method sensitivity. Accelerator mass spectrometry is emerging as an enabling technology for assessing mass balance with very low doses of radioactivity, with potential application in very early, if not the earliest, human trials. This chapter focuses on clinical drug metabolism studies using labeled or unlabeled materials to assess disposition pathways and excretion routes of development-stage candidates.