Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14+monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-a isoforms, HIF-1b, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1a in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1b and IL-17 since targeted down regulation of HIF-1a via short interfering RNA or a HIF-1a inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1a levels and modified cytokine production. These data suggest that increased activity of HIF-a isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.