Despite more than 50 years of research, the etiology of depressive illness remains unknown. A hypothesis that has been central to much work in pharmacology and electrophysiology is that depression is caused by dysfunction in the serotonergic signaling system. In recent work, with Janet Best (OSU) and H. Frederik Nijhout (Duke), a mathematical model of a serotonergic synapse was created to study regulatory mechanisms in the serotonin system. After an introduction to the serotonin system, the model will be described as well as comparisons to experimental results. We will discuss why it is so difficult to understand the mechanism of efficacy of selective serotonin reuptake inhibitors (SSRIs). We will present predictions of the model as well as a new hypothesis for the mechanism of action of the SSRIs.