Various pharmacological strategies have been developed to treat such refractory depression, of which combination therapies with antidepressants are one of the most important. This article reviews both benefits and risks of all known antidepressant combination strategies. The relevant literature was identified by means of a computerized MEDLINE research on the years 1990-2006 and scanning of review articles. The use of antidepressant combinations to overcome refractory depression is a common strategy in practice. Many antidepressants can be usefully combined especially if they engage separate mechanisms of action--like SSRIs with Reboxetine, Bupropion, Mirtazapine and Tricyclics--or on the other hand--Tricyclics with MAO-Inhibitiors. Combination strategies are effective treatment options, however they do have potential safety risks due to pharmacokinetic and pharmacodynamic interactions. Combinations including MAOIs can cause serotonin syndrome, and some SSRIs like Fluoxetine may elevate tricyclic plasma levels with the consequence of an increased risk of toxicity. The distinct knowledge of available antidepressant combination strategies may help to increase response--as well as remission rates in therapy resistant depression. However, further research is urgently needed to determine relative efficacy.