Glucocorticoids are a class of systematically secreted hormones, vital for mammalian life, which are intensively investigated for more than 80 years. They regulate multiple body processes like metabolism, fluid homeostasis, immune and stress system responsivity, as well as brain function. Glucocorticoids have a complex rhythm by which they are released to circulation from the adrenal cortex. The hormone exhibits a circadian variation, with high hormonal levels being secreted just prior and during the active part of the day, and progressively lower and lower amounts being released during the inactive part of it. Underlying this diurnal variation there is a more dynamic, ultradian rhythm composed of frequent episodes of glucocorticoid secretion (hormonal pulses). Accumulating evidence from observational, in silico, in vitro and in vivo, preclinical and clinical studies suggest that both aspects of glucocorticoid rhythmicity are preserved among mammalian species and are important for brain function. The central nervous system is exposed to both aspects of the hormonal rhythm and has developed mechanisms able to perceive them and translate them to differential cellular events, genomic and non-genomic. Thus, glucocorticoid rhythmicity regulates various physiological neural and glial processes, under baseline and stressful conditions, and hormonal dysrhythmicity has been associated with cognitive and behavioural defects. This raises a number of clinical implications concerning (i) glucocorticoid involvement in neuropsychiatric disease and (ii) improving the therapeutic efficacy or expanding the role of glucocorticoid-based treatments in such conditions.