The pathophysiological mechanisms of leakage, synthesis, and decreased removal of enzyme from blood all play a role in explaining why serum enzymes increase in disease. This presentation has focused on increased synthesis as an important and perhaps major source of increased serum enzymes. The second key point has to do with the reference standard. There is tremendous sophistication in the field addressed to the numerator, that is, biochemical units. The natural tendency is to focus attention on what we want to know in the numerator, the enzyme changes in the tissue. In so doing, however, we tend to ignore the changes of the reference standard in the denominator, which influence the final result as much as the numerator. The following recommendations are made: uniformity, enzyme activities referable to morphological units, and basic biological significance. Total organ per gram initial body weight is recommended as the optimal reference standard whenever possible. If this were done, perhaps we could then resolve the dilemma of the poor understanding of why serum enzymes change in disease. We would, thereby, be better equipped to bring the major part of biochemical pathology out of its infancy as described by Farber.