Hypoxia is the decreased level of oxygen in tissues, and it is present in the majority of solid tumors, mainly because of the inadequate blood supply and rapid tumor growth. There are two kinds of hypoxia, acute and chronic hypoxia, which besides of the pathophysiologic differences, also have different biological and clinical consequences. Activation of hypoxia signaling pathway, which mainly occurs through HIF-1, stimulates neoangiogenesis, alters tumor metabolism, promotes a more aggressive tumor behavior and significantly affects its responsiveness to therapy. Various evidence suggest that hypoxia induces transcription of tumor progression genes leading to increased tumor cell proliferation and metastatic potential. Hypoxia is believed to be the key microenvironment factor that induces tumor metastasis Besides its connectivity with more aggressive tumor phenotype, hypoxia also induces resistance of tumorous tissue against radiotherapy, chemotherapy and other treatment modalities. Because of that, there are many studies of combination of the standard therapeutic treatment (radiotherapy, chemotherapy) and drugs that have effect on the HIF-1 (HIF-1 inhibitors), or on the glucose metabolism. However, to select patients suitable for such treatment (combination of radiotherapy and HIF-inhibitors), it is necessary to show tumor hypoxia through imaging techniques (CT, MRI, PET), whereby PET being most useful technique. Better understanding of molecular pathways in hypoxia can contribute to more effective treatment options, along with the establishment of useful prognostic and predictive factors.