Toll-like receptors (TLRs) are responsible for the recognition of a variety of microbial pathogens and the initial induction of immune and inflammatory responses. These responses are normally restricted by the adrenally produced glucocorticoid hormones which provide a feedback mechanism to curb unabated inflammation. Glucocorticoids act through a ligand-dependent transcription factor—the glucocorticoid receptor (GR), which engages in a complex network of protein:protein and protein:DNA interactions ultimately activating or repressing target gene transcription. Not surprisingly, multiple mechanisms account for the glucocorticoid interference with TLR signaling including enhanced expression of the natural inhibitors of TLR pathways, direct repression of TLR-activated transcriptional regulators and cross-utilization of cofactors essential for both GR and TLR signaling. Here we discuss recent and unexpected examples of crosstalk between the two transcriptional networks and the emerging role of GR in the regulation of innate immunity.