Aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) play crucial role in the regulation of drug metabolizing enzymes and in many essential physiological processes. Cellular signaling by these receptors shares several functional and regulatory features. Here we investigated regulatory cross-talk between these two receptors. Human hepatoma cells (HepG2) were the model of choice. We analyzed the effects of dexamethasone (DEX) and dioxin (TCDD) on i) expression of AhR and GRalpha mRNAs; ii) levels of AhR and GR proteins; iii) transcriptional activities of AhR and GR in reporter assays; iv) 7-ethoxyresorufin-O-deethylase activity (EROD). We found that both DEX and TCDD affected AhR and GR mRNAs expression, proteins levels and transcriptional activities in HepG2 cells. These effects on cellular signaling by AhR and GR comprised up-/down-regulation of gene expression and ligand-dependent protein degradation. We conclude that interactive regulatory cross-talk between GR and AhR receptors in HepG2 cells defines possible implications in physiology and drug metabolism. Future research should be focused on the investigation of AhR-GR cross-talk in various normal human cells and tissues both in vitro and in vivo.