The hypoxia-inducible factor-1 (HIF-1) is an oxygen-regulated transcriptional activator playing a pivotal role in mammalian physiology and disease pathogenesis, e.g., HIF-1 is indispensable in a broad range of developmental stages in different tumors. Its post-translational regulation via PHDs under the influence of hypoxia is widely investigated and accepted. Different non-hypoxic stimuli such as lipopolysaccharides (LPS), thrombin, and angiotensin II (Ang II), have been proven to enhance HIF-1 levels through activation of regulative mechanisms distinct from protein stabilization. Some of these stimuli specifically regulate HIF-1α at the transcriptional, post-transcriptional, or translational level, whereas others additionally influence post-translational modifications. Thus, it is difficult for the investigators to discern the impact of the different mechanisms leading to functional HIF-1 protein. Nevertheless, profound knowledge of additional regulatory networks appears to depict new therapeutic opportunities and thus is an interesting and important field for further investigations. J. Cell. Physiol. 227: 514–524, 2012. © 2011 Wiley Periodicals, Inc.