Clinical depression is a chronic, recurrent mood disorder that causes significant disability and disease burden throughout the world. Not surprisingly, there is an enormous demand for finding (a) appropriate medications and devices for treating the clinical symptoms and (b) the underlying molecular mechanisms of the disease. Currently, most therapeutic treatments of depression indirectly target the serotonin and norepinephrine systems of the brain, as these neurotransmitters have long been considered promising and mechanistically relevant to the etiology of mood disorders. However, selective serotonin reuptake inhibitors such as sertraline, fluoxetine and paroxetine do not always substantially improve clinical outcome, and when they do show efficacy, it takes weeks of treatment to achieve an appreciable clinical effect. These observations suggest that a serotonin and norepinephrine hypothesis of depression is incomplete at best, and that novel, rapid onset therapeutic options for depression must be considered. In this review, we highlight several potential new drugs for clinical depression based on recent discoveries about the neurotransmitter glutamate and its family of receptors. Moreover, we discuss the possibility that glutamate-based antidepressant drugs might affect covalent histone modifications including acetylation in areas of the brain (e.g., pre-frontal cortex, hippocampus) thought to be relevant for the pathogenesis of affective disorders. If so, histone hyperacetylation and thus chromatin remodeling might be important regulatory mechanisms underlying the effects of ketamine and other N-Methyl-D-Aspartate receptor antagonist drugs. Chromatin remodeling may represent a non-serotonin/norepinephrine therapeutic strategy for treatment of clinical depression, a strategy that may also be appropriate in the context of drug discovery and drug development.