Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes and can be opposed by deubiquitinases (DUBs), which have emerged as promising drug targets. Apart from protein localization and activity, ubiquitylation regulates degradation of proteins, among them hypoxia-inducible factors (HIFs). Thereby, various E3 ubiquitin ligases and DUBs regulate HIF abundance. Conversely, several E3s and DUBs are regulated by hypoxia. While hypoxia is a powerful HIF regulator, less is known about hypoxia-regulated DUBs and their impact on HIFs. Here, we review current knowledge about the relationship of E3s, DUBs, and hypoxia signaling. We also discuss the reciprocal regulation of DUBs by hypoxia and use of DUB-specific drugs in cancer.