According to the 10th edition of the IDF Diabetes Atlas, 537 million people suffered from diabetes in 2021, and this number will increase by 47% by 2045. It is estimated that even 30-40% of these individuals may develop diabetic kidney disease (DKD) in the course of diabetes. DKD is one of the most important complications of diabetes, both in terms of impact and magnitude. It leads to high morbidity and mortality, which subsequently impacts on quality of life, and it carries a high financial burden. Diabetic kidney disease is considered a complex and heterogeneous entity involving disturbances in vascular, glomerular, podocyte, and tubular function. It would appear that hypoxia-inducible factors (HIF)-1 and HIF-2 may be important players in the pathogenesis of this disease. However, their exact role is still not fully investigated. In this article, we summarize the current knowledge about HIF signaling and its role in DKD. In addition, we focus on the possible effects of nephroprotective drugs on HIF expression and activity in various tissues.