Simple SummaryHyperglycemia is a hallmark of diabetes mellitus and contributes to several complications of this disease, such as diabetic retinopathy, diabetic nephropathy, and diabetic foot ulcer. Epidemiological evidence showed that patients suffering from diabetes are at a significantly higher risk for the development of cancer; in addition, the high glucose condition can reduce the efficacy of anticancer therapies. Therefore, uncovering novel molecular mechanisms deregulated by high glucose could give insights into the progression of high glucose-related pathologies other than the development of more efficient anticancer therapies. In this regard, homeodomain-interacting protein kinase 2 (HIPK2) has recently been disclosed in both high glucose-induced cancer resistance to chemotherapies and in diabetic complications, which will be summarized in the present review.AbstractHIPK2 is an evolutionary conserved protein kinase which modulates many molecular pathways involved in cellular functions such as apoptosis, DNA damage response, protein stability, and protein transcription. HIPK2 plays a key role in the cancer cell response to cytotoxic drugs as its deregulation impairs drug-induced cancer cell death. HIPK2 has also been involved in regulating fibrosis, angiogenesis, and neurological diseases. Recently, hyperglycemia was found to positively and/or negatively regulate HIPK2 activity, affecting not only cancer cell response to chemotherapy but also the progression of some diabetes complications. The present review will discuss how HIPK2 may be influenced by the high glucose (HG) metabolic condition and the consequences of such regulation in medical conditions.