New systemic cancer therapies are increasingly oriented towards specific signaling pathways involved in carcinogenesis. However, these new treatments may lead to disorders of glycemic homeostasis ranging from glucose intolerance, diabetes or the occurrence of severe acute hyperglycemic syndrome due to blockade of certain pathways common to glucose metabolism. This article discusses the estimated frequency of new-onset diabetes, the pathophysiological mechanisms as well as the diagnostic, therapeutic, monitoring and prognostic management of glycemic dysfunction in patients treated with these novel systemic cancer therapies.