Glucocorticoids (GC) are steroid hormones with important implications in the treatment of various inflammatory and autoimmune diseases. At the same time GC are known to have numerous side-effects. Endogenous GC are predominantly produced by the adrenal glands, and adrenal-derived GC serve important functions in the regulation of development, metabolism, and immune regulation. The last two decades of research have led to the identification of numerous alternative sources of extra-adrenal GC synthesis. Among other tissues the intestine and lung are capable of locally producing considerable amounts of immunoregulatory GC. This local steroidogenesis in these mucosal tissues appears to be regulated by transcription factors and mediators different from those in the adrenals, likely reflecting an adaptation to the local requirements and conditions. Here we summarize the current knowledge about the extra-adrenal GC synthesis in the mucosal tissues, with special emphasis on the intestinal epithelium, and its implication on the regulation of immune homeostasis and inflammatory processes.