Oxidative metabolism by the cytochromes P450 (CYPs) is the most common metabolic pathway of drug clearance. Medicinal chemists in drug discovery often synthesize analogs of lead molecules to reduce clearance due to metabolism. One method generally used when attempting to reduce CYP metabolism is to identify the site of modification to 'block' it. Substituting fluorine in the place of hydrogen at metabolically labile positions, for example, is a common approach, although deuterium can also be considered here for simplicity. In this case, the rate of metabolism via a specific pathway is attenuated, but the rate of overall substrate consumption or overall clearance is not significantly altered, due to a compensatory increase in the rate of formation of an alternate metabolite. The concepts and evidence behind this phenomenon as it relates to complexities in blocking metabolic clearance are presented herein.