The term atypical depression as a preferentially monoamine oxidase inhibitor (MAOI)-responsive state was first introduced by West and Dally in 1959. Further characterization of this syndrome and its responsiveness to antidepressants came to occupy the attention of many psychopharmacologists for the next 30 years. Different portrayals of atypical depression have emerged, for example, nonendogenous depression, phobic anxiety with secondary depression, vegetative reversal, rejection-sensitivity, and depression with severe chronic pain. Consistency across or within types has been unimpressive, and no coherent single type of depression can yet be said to be "atypical." In successfully demonstrating superiority of MAOI drugs to tricyclics, the Columbia (or DSM-IV) criteria have established their utility and become widely adopted, but other criteria have also passed this test. In this "post-MAOI" era, no novel compound or group of drugs has been clearly shown to have good efficacy in atypical depression, leaving the treatment of atypical depression as an unmet need.