Psychiatric disorders such as depression are known to be under a degree of genetic influence, but the specific variants contributing to this heritability remain largely unknown. The serotonin transporter gene has received the most attention in relation to depression, either alone or in conjunction with exposure to stressful life events (i.e. a gene x environment interaction), whereas neuroimaging studies have suggested an association with amygdala activation. There is also some evidence that this gene may predict antidepressant response. However, each of these literatures has followed a similar course of initial promise giving way to an inconsistent pattern of replications and nonreplications. In parallel, whole genome approaches have begun to provide robust findings and novel insights into the mechanisms of common disease. One of these insights is that the genetic architecture of common disease phenotypes such as depression comprises a very large number of common variants of very small effect, possibly together with a smaller number of rare variants of larger effect. This is at odds with the apparently large effect of the serotonin transporter gene reported in some studies. Taken together, it is unlikely that the serotonin transporter gene plays a major role in depression. Future single locus analyses should be informed by more robust findings derived from whole genome methods.