Thyroid hormones are important regulators of differentiation, growth, metabolism and physiological function of virtually all tissues. Active thyroid hormone 3,3',5-Triiodothyronine (T₃) affects expression of genes that encode for angiogenic proteins like adrenomedullin (ADM) or vascular endothelial growth factor (VEGF) and erythropoietin (EPO) as well as for glucose transporters (GLUT) and phospho fructokinase (PFK) that determine glucose utilisation. Interestingly, those target genes are also hypoxia inducible and under the control of the oxygen-dependent transcription factor Hypoxia Inducible Factor 1 (HIF-1). We and others have reported that T₃ stimulates HIF-1 activation which intimately links T₃ and HIF-1 induced gene expression. Herein, we studied intracellular pathways that mediate HIF-1 regulation by T₃. We found that T₃ dependent HIF-1 activation is not limited to hepatoma cells but is also observed in primary human hepatocytes, kidney and lung carcinoma cells. T₃ increased the HIF-1 subunit mRNA and protein within a few hours through activation of the thyroid hormone receptor retinoid X receptor heterodimer since knockdown of each of the partners abrogated the stimulation by T₃. However, T₃ had no direct effect on transcription of HIF-1 but activation of the TR/RXR-heterodimer by T₃ stimulated expression of hepatic leukemia factor (HLF) which increases HIF-1 gene expression.