Clinicians have few evidence-based options for the management of bipolar depression and even fewer for treatment-resistant bipolar depression (TRBD). To date, relatively few studies have examined the next-step treatment strategies for TRBD and no clear guidelines or unequivocal algorithms exist in order to inform clinicians on what to do when the first approved therapies fail. Although research on optimal treatments for bipolar depression has been increasing, a lack of a sufficient database and disagreements about the classic treatment of bipolar depression have precluded a consensual treatment algorithm for treatment-resistant bipolar depression, and well-designed studies on TRBD still lack (Vieta & Colom, 2010). Until recently, the algorithms for TRBD were undistinguishable from TRD’s, despite the absence of good evidence supporting the use of antidepressants in patients with bipolar disorder. In 2009, Pacchiarotti et al proposed a new definition for TRBD (Pacchiarotti et al, 2009). As a general rule, the management of TRBD includes the same operational steps as in unipolar TRD, but with totally different treatment options. Strategies include optimization of the dosage of the current drug, combination or augmentation and switch strategies, that is, introducing a new drug to replace the old one. However, the definition of TRBD is not based on lack of response to antidepressant, but to drugs such as quetiapine, lithium, and lamotrigine. This lecture will provide a challenging overview of the current state-of-the art in the management of TRBD and future developments.