Understanding the metabolism of a novel drug candidate in drug discovery and drug development is as important today as it was 30 years ago. What has changed in this period is the technology available for proficient metabolite characterization from complex biological sources. High-efficiency chromatography, sensitive MS and information-rich NMR spectroscopy are approaches that are now commonplace in the modern laboratory. These advancements in analytical technology have led to unequivocal metabolite identification often being performed at the earliest opportunity, following the first dose to man. For this reason an alternative approach is to shift from predicting and extrapolating possible human metabolism from in silico and nonclinical sources, to actual characterization at steady state within early clinical trials. This review provides an overview of modern approaches for characterizing drug metabolites in these early clinical studies. Since much of this progress has come from technology development over the years, the review is concluded with a forward-looking perspective on how this progression may continue into the next decade.