Many behavioural overlaps exist in the effects of norepinephrine (NE), serotonin (5-HT) and dopamine, and it is now thought that complex behaviour patterns may reflect interactions among these neurotransmitters. There is a wide variety of evidence for the pivotal role of the NE system in the pathogenesis and treatment of major depression. This paper discusses the functioning of the NE system, specifically the regulation of neuronal firing and the postsynaptic responses to NE, which can be controlled by norepinephrine reuptake inhibitors and other drugs. In addition, interactions between NE neurons and 5-HT neurons have implications for the treatment of depression and anxiety disorders. Specifically, the projections of 5-HT neurons have an inhibitory effect on NE neurons, which means that selective serotonin reuptake inhibitors also affect the NE system. Further experiments and long-term studies will increase knowledge of the mechanisms of action of various psychopharmacologic agents and may eventually lead to better therapeutic choices.