Glucocorticoids are among the most widely prescribed drugs used for human diseases, and are especially commonly used in autoimmune diseases. Their use reflects their rapid and broad spectrum actions on immune cells, which in turn reflect the multiple mechanisms of cell activation upon which glucocorticoids impact. While inhibition of pro-inflammatory gene expression is a major effect of glucocorticoids, they also induce the expression of numerous molecules that exert regulatory influences on the immune system. Among these is glucocorticoid induced leucine zipper (GILZ), a recently described, highly glucocorticoid-induced, transcriptional regulatory protein which has important inhibitory effects on immune and inflammatory cell functions. In this review, we summarize knowledge of the actions of glucocorticoids relevant to autoimmune disease, and focus on the potential for greater understanding of the function of GILZ to facilitate discovery of new therapeutic options for these diseases.