Overdoses of tricyclic antidepressants (TCA's) are frequent and can be life-threatening due primarily to their cardiotoxic effects. These overdoses may be intentional, accidental, or even iatrogenic, with the latter due to the wide interindividual variability in elimination rates. Steady-state TCA plasma levels correlate well with tissue concentrations and permit adjustment of dosage to minimize the risk of iatrogenic poisoning. Other factors increasing the risk of toxicity include age, cardiac status, and concomitant use of drugs. Cardiotoxicity results from direct membrane actions of TCA's at high tissue concentration. Treatment of TCA overdose is first aimed at preventing absorption, then at hastening elimination by interfering with the enterohepatic recirculation. Although drugs can ameliorate certain toxic effects, indiscriminate use of purported antidotes can have deleterious results.