Glucocorticoids are universally prescribed as the drug of choice for the treatment of inflammatory and autoimmune disorders. These stress hormones act through their cognate glucocorticoid receptor to regulate transcription of various target genes. The mechanisms of glucocorticoid action are often cell type dependent and involve the regulation of thousands of genes. Glucocorticoids have a tremendous impact on the immune system during inflammation including effects on the plasticity, survival, and function of immune cells. This chapter highlights the dynamic effects of glucocorticoids in regards to both physiological and pathological conditions during inflammation. We address issues involving classical and alternative mechanisms of glucocorticoid inhibition, the effect on innate and adaptive immunity, glucocorticoid tissue-specific actions, and their role in target immune cells. © Springer International Publishing Switzerland 2017.