Hypoxia inducible factor-1 (HIF-1) is a master regulator under conditions of decreased oxygen availability. As a hypoxia inducible transcription factor HIF-1 is a heterodimer composed of the helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF- 1α and the aryl hydrocarbon nuclear translocator (ARNT) also known as HIF-1β. The HIF-1 transcriptional system senses decreased oxygen availability and transmits this signal into patho-physiological responses such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, as well as cell survival decisions. Among recent advances are the discoveries that reactive nitrogen species (RNS), oxygen species (ROS), cytokines, and growth factors participate in stability regulation of HIF-1α and HIF-1 transactivation during normoxia. Here we summarize current knowledge and existing concepts that help to understand how NO affects protein accumulation of HIF-1α. Considering the fundamental role of radicals, especially NO, as signaling molecules makes HIF-1α an attractive target under conditions of NO formation that may be attributed to both, physiology and pathology. Although initial observations showed that NO inhibits hypoxia-induced HIF-1α stabilization and HIF-1 transcriptional activation, later studies indicated that exposure of various cells to chemically diverse NO donors or conditions of endogenous NO formation under normoxic conditions induced HIF-1α accumulation, HIF-1-DNA binding, and activation of downstream target gene expression. These contrasting situations evoked by NO provide insights into basic chemical reactions, biochemical signal transduction pathways with broad implications for medicine.