This chapter offers a current assessment of the relevance of new findings on the pharmacodynamics and pharmacokinetics of active metabolites of the tricyclic antidepressants. The assessment of TCA actions that may be additive, synergistic, or antagonistic requires precise knowledge of pharmacodynamic potency and control of pharmacokinetic behavior. Simple assumptions about the behavior of ratios of active forms across the populations are inappropriate. Careful pharmacokinetic control is necessary, especially considering that such variables as age, race, illness and other drugs can subtly influence the overall effect by influencing a single active form. The hydroxy metabolites are most susceptible since both their formation and elimination utilize independent variable pathways. Nonetheless, it is now possible to quantitate all known active forms of TCAs. Clinical investigation of the relationship between these forms and specific biochemical effects should provide advances in our understanding of antidepressant mechanisms. On the basis of available data of this type, we conclude that an intensified effort to understand effects secondary to NE uptake inhibition alone would be especially valuable.