The Siah ubiquitin ligases are members of the RING finger E3 ligases. The Siah E3s are conserved from fly to mammals. Primarily implicated in cellular stress responses, Siah ligases play a key role in hypoxia, through the regulation of HIF-1α transcription stability and activity. Concomitantly, physiological conditions associated with varying oxygen tension often highlight the importance of Siah, as seen in cancer and neurodegenerative disorders. Notably, recent studies also point to the role of these ligases in fundamental processes including DNA damage response, cellular organization and polarity. This review summarizes the current understanding of upstream regulators and downstream effectors of Siah.