The hypoxia-inducible factor HIF-1 has been shown to be mandatory for the cellular adaptation to hypoxia. In addition, evidence has been provided that HIF-1 can mediate various stress responses and that it may play an important role under inflammatory conditions even independently of hypoxia. HIF-1 is a heterodimer consisting of an alpha subunit which is subject to tight regulation, and a beta-subunit, also termed ARNT, which appears to be constitutively expressed. In addition to the complex network controlling the cellular content of HIF-1alpha at the level of protein stability, recent evidence showed that HIF-1alpha levels can also be regulated at the mRNA level. In fact, transcriptional regulatory networks seem to be an additional way of controlling HIF-1alpha levels and may open new therapeutic options to modulate HIF-1alpha also under non-hypoxic conditions.