The traditional dose-response method of medication adjustment depends on several assumptions that are not met in the case of tricyclic antidepressants (TCAs), which makes therapeutic drug monitoring (TDM) particularly useful with these drugs. TDM can facilitate treatment by providing objective guidelines for dose adjustment. It provides a means of assessing compliance, ensuring an effective concentration, and avoiding toxicity. The latter is an often-overlooked benefit of therapeutic monitoring of TCAs and yet is just as important as improving response. The cardiac and central nervous system toxicity of TCAs is concentration-dependent and potentially life-threatening. Such toxicity will predictably occur in up to 5% of patients on standard antidepressant doses of TCAs when TDM is not used to rationally adjust the dose. Without TDM, such toxicity is difficult to detect early. A cost/benefit analysis supports the cost effectiveness of TDM as a standard part of TCA chemotherapy when doses in the 100-300 ng/day range are used.