Glucocorticoids regulate numerous distinct physiological processes, most of which rely on the ability of the hormone-bound glucocorticoid receptor (GR) to change the expression of target genes in a cell- and promoter-dependent manner. The transcriptional activity of GR depends on coactivators that regulate transcription by remodeling chromatin or by facilitating the recruitment of the basal transcriptional machinery. Coactivators are often part of multiprotein complexes that are not specific for GR but also mediate the activity of other nuclear receptors (NRs) and unrelated transcription factors. Surprisingly, recent results reveal that the activity of coactivators might contribute to the receptor, promoter and cell specificity of NR action. The emerging picture shows coactivators as flexible, but precise, coordinators of complex and dynamic networks, in which transcriptional regulation by GR and other NRs is linked to other signaling pathways.