As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to increase in drug discovery portfolios. Currently available in vitro tools have limited resolution below a certain intrinsic clearance value, which can lead to overestimation of clearance and dose and underestimation of half-life. Significant advances have been made in recent years and novel approaches have been developed to address the challenges of low clearance in drug discovery, such as the hepatocyte relay method, use of qNMR-based standards of biosynthesized drug metabolites to permit monitoring metabolite formation, coculture hepatocyte systems, and the time depending modeling approach. Future development in the field will enable faster, more precise, and lower cost profiling of the properties of low-clearance compounds for intrinsic clearance, metabolite identification, and reaction phenotyping.