Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression.