This chapter defines the concept of treatment-resistant depression (TRD), which is distinguished from 'pseudo-TRD' resulting from either misdiagnosis, unrecognized concurrent medical and psychiatric illnesses, inadequate antidepressant treatment or unrecognized pharmacokinetic factors interfering with adequate treatment. In formulating a treatment approach to TRD, some type of illness measurement or 'staging' is useful as a measure of the level of severity of the disease. A clear majority of antidepressant treatments were inadequate and failed to meet minimal therapeutic requirements. The two major factors to be reviewed in determining trial adequacy are medication dosing and trial duration. The chapter reviews several approaches for optimizing treatment and minimizing resistance in depressed patients, as well as some suggested approaches for directly treating TRD. Finally, a careful consideration and pursuit of all treatment options at each stage of TRD with ongoing diagnostic reevaluation permits the clinician to handle the difficult syndrome of TRD more effectively.