There are no agreed criteria for treatment-resistant depression, but the failure to respond adequately to two successive courses of monotherapy with pharmacologically different antidepressants, given in an adequate dose for sufficient time is one pragmatic definition. Inherent within this definition are notions of what constitutes an adequate dose of drug, the length of treatment and pharmacological specificity of treatments. When these factors are accounted for, treatment resistance may be encountered in 15-20% of patients. In attempting to treat such patients a number of pharmacological strategies have been adopted and some are briefly reviewed. Psychosurgery may have a role to play in cases of absolute treatment resistance.