The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect. Accordingly, the DRN has been strongly associated with brain dysfunction, especially mood disorders such as depression, but also Alzheimer's disease. The DRN's most abundant transmitter, serotonin, has received the most attention in studies on both normal brain function and disease, and lately its involvement in the regulation of neuroplasticity has been under particular scrutiny. This chapter begins with a systematic overview of what we currently know about the anatomy of the DRN and its neurons, including their ascending projections. It continues with a review of the transmitters of the DRN, followed by a discussion on the connection between the DRN and neuroplasticity. Special emphasis is put on serotonin and its central role in neuroplasticity, which is proving to be of high priority in unraveling the full picture of the cellular mechanisms and their interconnections in the etiology of major depression and Alzheimer's disease.