The hypothalamic-pituitary-adrenal (HPA) axis plays a primary role in stress response through the regulated secretion of the glucocorticoid hormone cortisol. Diseases of cortisol dysregulation such as Cushing’s syndrome (hypercortisolemia) and Addison’s Disease (hypocortisolemia) are both associated with depression. Based on this we, and others, have hypothesized that mutations in the genes for the glucocorticoid receptor (GR), the closely related mineralocorticoid receptor (MR), and regulatory proteins associated with cortisol or GR function may contribute to depression in the absence of hyper- or hypo-cortisolemia. Our study investigated the genotypic frequency in the clinical population of several single nucleotide polymorphisms (SNPs) that affect GR and MR sensitivity to cortisol binding. Buccal swab DNA samples were acquired from patients clinically diagnosed with depression and from a random population. Extracted DNA was analyzed utilizing multiple allele-specific polymerase chain reactions to determine genotypic frequency of SNPs associated with hypersensitivity or resistance to cortisol. In addition, patients suffering from depression completed the multiple measures of depression and anxiety. Preliminary results have shown that a specific allele of the GR BclI polymorphism (rs41423247) is more frequently seen in depressed patients compared to a random population and is also associated with elevated measures of depression. Understanding the role of geneotypic variation in cortisol function could lead to more specific and targeted therapies for depression with the goal of improving patient outcomes.