The depressive disorders (DDs) and bipolar and related disorders (BRDs) have their own chapter in the DSM-5-TR (Diagnostic and Statistical Manual of Mental Disorder, 5th Edition, Text Revision). Both DDs and BRDs have significant impact on patients’ life and society. In 2019, globally, DDs were ranked #13 of all ages in disability adjusted life years (DALYs) and #2 in years lived with disability (YLDs) among the 369 diseases. BRDs were ranked #67 in DALYs and #28 in YLD. Clinical studies have shown that correct diagnosis and adequate treatment of mood disorders can improve functioning and prevent disability. The focus of this chapter is to discuss the diagnosis of DDs and BRDs based on the DSM-5-TR and the differential diagnosis between major depressive disorder (MDD) also known as unipolar depression (UPD) and bipolar depression (BPD). For treatment, commonly used pharmacological and nonpharmacological treatments will be discussed.