Glucocorticoids have been the mainstay of anti-inflammatory therapy for the past 50 years despite the significant risks associated with their long-term use. Recent research into the molecular mechanisms of action of these compounds can be aggregated into two major themes: first, those that focus on the involvement of the glucocorticoid receptor in regulating the transcription of pro-inflammatory genes; and second, studies that seek to identify alternative pathways of glucocorticoid action either via the induction of anti-inflammatory mediators or through rapid non-genomic mechanisms. Understanding the temporal-spatial patterns of these multiple mechanisms on relevant cell types will be key to explaining the profound effects that these four-ring steroids exert on the inflammatory process.