Previously, it has been suggested that hypothalamic-pituitary-adrenal (HPA) axis dysregulation and, as a consequence, increased cortisol levels, is not only a state phenomenon, but may also be a trait phenomenon in mood disorders. Cortisol exerts its effects mainly by binding to the glucocorticoid receptor (GR) and, of particular interest in certain brain regions, the mineralocorticoid receptor (MR). Several GR polymorphisms have been shown to be associated with altered sensitivity of the HPA axis. Recently, the GR polymorphisms BclI and ER22/23EK have been associated with unipolar depression in several studies. In addition, the ER22/23EK polymorphism seems to be associated with a decreased risk of dementia in healthy individuals. Also, during a depressive episode, carriers of this ER22/23EK variant demonstrated a tendency toward better cognition, as measured by divided attention tests. In this overview, currently known clinically relevant GR and MR polymorphisms are discussed in relation to mood disorders (both unipolar depression and bipolar disorder) and cognitive function.