The majority of treatments for neuropsychiatric disorders have been based on serendipitous discoveries, with little understanding of the pathogenic and pathophysiological mechanisms underlying these disorders. As many of these disorders are sensitive to stress, an understanding of the physiology of stress is important in avoiding and reversing stress-sensitive disorders. Increased understanding of the glutamatergic synapse has revealed a system that is affected by both stress and multiple neuropsychiatric treatments, suggesting a possible convergent target in these disorders. This chapter reviews how traditional neuropsychiatric treatments affect the glutamatergic synapse, and how future therapies may be developed to more directly target this system.