Depression is one of the most common mental disorders, it affects about 5–17% of the population. Depressive disorders are a serious economic and social problem. Depression has a significant impact on the employment status, financial success and interpersonal relationships. It is the reason for the greatest number of days of absence from work among all diseases. Patients who do not respond to standard antidepressant treatment cost twice as much as patients who do respond to treatment (response to standard antidepressant treatment occurs only in 60–70% of patients suffering fromdepressivedisorder). According to epidemiological data, even one-third of patients may have treatment-resistant depression, which is defined as depressive disorder in adults who have not responded to at least two different antidepressants (used at the right dose for the appropriate period) in the current episode of moderate to severe depression. The purpose of this publication is to present the problem of drug resistance in depression and to present strategies for dealing with treatment-resistant depression.