The von Hippel-Lindau (VHL) protein is a tumor suppressor which functions as the substrate recognition component of the multi-subunit Cullin RING E3 ubiquitin ligase complex (CRL2 VHL ). Besides VHL, the CRL2 VHL complex includes the central scaffold subunit Cullin 2, Elongin B (EloB) and Elongin C (EloC) as adaptor subunits, and RING-box protein 1 (Rbx1). As the largest family of E3 ligases, CRLs are responsible for ~20% of all ubiquitination events through the ubiquitin-proteasome system (UPS), a cellular machinery implementing the degradation of intracellular protein targets, such as short-lived, damaged, misfolded, and also oxidized proteins. The conjugation of the small protein ubiquitin to the target proceeds via a three-step cascade mechanism. In the first step, the carboxyl group of Gly76 of ubiquitin is ATP-dependently attached to a cysteine of a ubiquitin-activating enzyme (E1). Subsequently, the activated ubiquitin is transferred by a transacylation reaction to a cysteine residue of a ubiquitin-conjugating enzyme (E2) and then irreversibly transferred to a lysine residue of a target protein, a key step that is catalyzed by an E3 ligase. The consecutively generated polyubiquitin chain serves as a tag for target recognition and degradation by the 26S proteasome. Aberrant regulation of CRLs and the UPS pathway are linked to a wide range of human diseases, such as cancer, diabetes, neurodegenerative disorders, and inflammation. The importance of therapeutic interventions is evidenced by the development of proteasome inhibitors, which, however, have several limitations as they lack specificity and may lead to the accumulation of a variety of cellular proteins. However, there are attractive therapeutic targets upstream of the proteasome, in particular E3 ligases, which endow the UPS system with high specificity. Respective drugs can act by disrupting or modulating the interaction of E3 ligases with their natural substrates. In recent years, the E3 ubiquitin ligase CRL2 VHL has attracted enormous attention, in particular, because of its key role in oxygen and hypoxia sensing. One of the most wellcharacterized substrates of VHL is the hypoxia-inducible factor-1α (HIF-1α). This transcription factor regulates numerous human genes, including those related to the maintenance of oxygen homeostasis. HIFs serve as master regulators of hypoxic signaling. They function as heterodimers consisting of two subunits, the oxygen-dependent HIF-α subunit, of which three isoforms are known in humans (HIF-1α, HIF-2α, and HIF-3α), and the constitutively expressed oxygen-independent HIF-β subunit. Under normoxia, two proline residues (Pro402 and Pro564) of HIF-1α undergo post-translational modification by oxygen-and iron-dependent prolyl hydroxylase domain (PHD) enzymes, members of the EglN family of dioxygenases. HIF-1α hydroxylation triggers molecular recognition by VHL, leading to ubiquitination and subsequent degradation of HIF-1α via the proteasomal pathway. In contrast, under hypoxic conditions, PHDs are inactive, HIF-1α remains unhydroxylated and escapes VHL recognition, leading to the accumulation of HIF-1α. Stabilized HIF-1α can translocate to the nucleus, where it forms a heterodimer with the HIF-1β subunit, which binds to specific hypoxia-responsive elements (HREs) promoting the transcription of target genes (Figure ). HIF stabilization and concomitant alterations in gene expression constitute a further opportunity for therapeutic intervention. It can be elicited with PHD inhibitors, that prevent the hydroxylation of HIF. Such drugs are already in clinical use for the treatment of renal anemia in multiple countries, and very recently the U.S. Food and Drug Administration approved the PHD inhibitor daprodustat in adults on dialysis suffering for anemia caused by chronic kidney disease. Figure . Mechanisms of oxygen-regulated activity of HIF-1α. Under normoxic conditions, PHDs use oxygen to hydroxylate HIF-1α, which is recognized by the CRL2 VHL complex, followed by ubiquitination and degradation. Under hypoxic conditions, non-hydroxylated HIF-1α accumulates and dimerizes with HIF-1β to a transcriptionally active complex.