Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is a cost-effective tool to increase efficacy and safety in patients suffering from major depressive illness. The concentration:antidepressant response relationships of nortriptyline, desipramine, and amitriptyline conform to a curvilinear relationship between concentration:antidepressant response; whereas, imipramine conforms to a linear relationship. Besides improving efficacy, TDM identifies the subset of patients who are at risk to develop excessive plasma TCA levels with potential resultant central nervous system and cardiovascular toxicity. Taking both the efficacy and safety data into account, cost:benefit analyses demonstrate that TDM is cost effective when used once as a standard aspect of care in the TCA treatment of patients with major depressive illness.