The present work aims at investigating the mechanisms of dysregulated ubiquitination of Hypoxia Inducible Factors (HIF-1α and HIF-2α) by mediating their proteasomal degradation through the promising PROTAC Technology, which has emerged as a powerful tool to rapidly and reversibly deplete endogenous proteins involved in many diseases. Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules able to specifically bind a target protein and induce its degradation by specifically recruiting a given E3 ubiquitin ligase. Contrary to protein inhibition, this technology benefits from the cell's own protein degradation pathway - Ubiquitin-Proteasome System (UPS) - to specifically remove labeled proteins. This work highlights the main advantages of PROTAC technology over protein inhibition but also critically showcases its challenges. We present a rational strategy to guide the design and synthesis of PROTACs targeting HIF-2α by starting from the X-ray crystal structure of the HIF-2α PAS-B domain and by taking inspiration from the most recent HIF-2α inhibitors.