SummaryAn effort has been made to summarize clinical selection criteria for therapeutic drug monitoring for the tricyclic antidepressants (TCAs). A clear understanding of this would increase the number of patients who benefit from TCA blood-level determinations. Depression has been defined in terms of the old and new nomenclature in an attempt to clarify the ambiguities that necessarily exist in such an all-encompassing classification of disease. The biogenic amine hypothesis of depression is briefly reviewed, followed by the effect of pharmacokinetic parameters on the establishment of steady-state blood levels. The protein binding of the TCAs and the resulting effect on free versus total drug levels is discussed. Pharmaceuticals and other factors known to affect TCA blood levels are mentioned. Following a discussion of anticholinergic side effects and cardiotoxicity, therapeutic ranges for various TCAs are reviewed as to our current level of understanding. The remainder of the paper explores patient selection criteria for future clinical studies attempting to establish a drug level—effect relationship. Recent case histories are supplied throughout the text to illustrate the various subjects addressed. They also instruct the clinician and the laboratory scientist as to the potential use of TCA blood-level monitoring in the treatment of depression.