The present invention relates to inhibitors of HIF-1 and HIF-2 and uses thereof. The present invention further relates to the inhibitors for use in treatment of diseases. An isolated polypeptide is provided, that prevents dimerization of HIF-1α with HIF-1β and HIF-2α with HIF-1β and/or inhibits the activity of HIF-1 and HIF-2, wherein the polypeptide comprises the amino acid sequence C-X1-X2-X3-Z-X4 (SEQ ID NO 1) and wherein X1, X2, X3 and X4 are any amino acid and wherein Z is leucine, valine of isoleucine or a non-natural derivative or leucine, valine or isoleucine. The isolated polypeptide prevents dimerization of HIF-1α with HIF-1β and HIF-2α with HIF-1β and inhibits the activity of HIF-1 and HIF-2 by binding to HIF-1α or HIF-1β and/or HIF-2α or HIF-1β.