The review is devoted to the experimental and clinical data analysis about the effectiveness and safety of drugs whose main target is the hypoxia-inducible factor HIF. The use of HIF inhibitors continues to be widely researched and is trying to enter practice in the treatment of cancers, such as the HIF-2α inhibitor belzutifan, which is approved for treatment of cancers associated with von Hippel–Lindau disease (VHL). HIF stabilizers can initiate preconditioning and be used in acute predictable myocardial or cerebral ischemia (during cardiac or vascular surgery). Long-term administration of some of them, in particular prolyl hydroxylase inhibitors, in the treatment of renal anemia cannot exclude the activation of neoangiogenesis, which is associated with the risk of pro-oncogenic effect as well as an increased risk of thrombosis and cardiovascular events.