The therapeutic technique of hemodialysis and the concept of clearance have both followed a long but instructive course of development. In addition, it recently has been shown that physiological changes occurring during hemodialysis have important clinical consequences both in the treatment of drug toxicity and in the selection of appropriate replacement doses of therapeutic drugs. Two major approaches for calculating hemodialysis clearance are currently used. The first approach, termed the recovery method is the “gold standard” that is recommended for use in the current US FDA draft guidance on the conduct of pharmacokinetic studies in patients with impaired renal function. The second approach, termed the A-V difference method, is used more commonly. Unfortunately, this method results in erroneous plasma clearance estimates when improper values for dialyzer flow are chosen. This constitutes a major pitfall that should be avoided in future studies.