Antidepressant-resistant major depression (AD-RD) is a great challenge for the treating clinician. The most widely accepted definition of AD-RD refers that the depressed patient does not show a clinically significant response after at least two adequate trials of different classes of antidepressants. In spite of the fact that there are several causes of AD-RD in general, there is increasing evidence that one of the most common sources of it is the unrecognized bipolar nature of the “unipolar” major depressive episode, when the patients receive antidepressant monotherapy - unprotected by mood stabilizers/atypical antipsychotics. While it is well documented that the optimal clinical response to antidepressants is much rare in bipolar I and II than in unipolar major depression, only the most recent clinical studies have focused on the boundaries between treatment-resistant unipolar major depressive disorder and bipolar disorder. The most widely noted conclusion of the prior studies on AD-RD is that if noncompliance, hypothyreosis, use of “depressiogenic” drugs and pharmacokinetic causes etc, can be excluded, antidepressant-resistance reflects the heterogeneity of depressive disorders and different subgroups of depressed patients respond (or do not respond) to different drugs. However, current psychopathological research on the complex relationship between unipolar depression and bipolar disorders show that the most common source of antidepressant-resistance in DSM-IV diagnosed unipolar major depression is the result of the subthreshold or unrecognized bipolar nature of the depressive episode and antidepressant-induced (hypo)manic switches, antidepressant-resistance and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity of the major depressive episode.