Existing treatments for depression usually take several weeks to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement or are treatment refractory even after long-term drug administration. Moreover, the increased risk of suicide is a serious public health concern that can occur particularly during the initial stages of antidepressant pharmacotherapy. Thus, there is an urgent need for therapeutics with improved efficacy that can exert their effects within hours or days of their administration. The pteridine tetrahydrobiopterin (BH4) is an essential co-factor for production of many neurotransmitters including serotonin. Given the pivotal role of BH4 in several processes fundamental to the pathobiology of mood disorders and the mechanisms of action of mood-regulating drugs, it is surprising that only a few studies have examined the potential role of BH4 pathway genes in individual variability in susceptibility to mood disorders and their treatment outcomes. Although previous studies have examined BH4 in these contexts, there were methodological shortcomings, as well as conflicting findings. However, more recent studies have provided new evidence for the importance of the BH4 pathway in mood disorders and their treatment. For example, the recent finding that the SSRI antidepressant paroxetine substantially affects the level of the protein sepiapterin reductase, which catalyzes the final step in the biosynthesis of BH4, in neural cells, has suggested a need to re-examine the BH4 pathway in the context of the pathobiology of mood disorders and, more importantly, as a potential target for mood-regulating drugs.