Activation of the glucocorticoid receptor (GR) by endogenous and synthetic glucocorticoids regulates hundreds of genes to control regulatory networks in development, metabolism, cognition and inflammation. Elucidation of the mechanisms that regulate glucocorticoid action has highlighted the dynamic nature of hormone signalling and provides novel insights into genomic glucocorticoid actions. The major factors that regulate GR function include chromatin structure, epigenetics, genetic variation and the pattern of glucocorticoid hormone secretion. We review our current understanding of the mechanisms that contribute to GR signalling and how these contribute to glucocorticoid sensitivity, resistance and side effects.