Abstract Dissociation between the healthy and toxic effects of cortisol, a major stress‐responding hormone has been a widely used strategy to develop anti‐inflammatory glucocorticoids with fewer side effects. Such strategy falls short when treating brain disorders as timing and activity state within large‐scale neuronal networks determine the physiological and behavioral specificity of cortisol response. Advances in structural molecular dynamics posit the bases for engineering glucocorticoids with precision bias for select downstream signaling pathways. Design of allosteric and/or cooperative control for the glucocorticoid receptor could help promote the beneficial and reduce the deleterious effects of cortisol on brain and behavior in disease conditions.