Diabetes mellitus is a complex metabolic disease characterized by high blood sugar levels. Different pathogenic processes are involved in the etiology of the disease. Indeed, chronic diabetes hyperglycemia is often associated with severe long-term complications including cardiovascular symptoms, retinopathy, nephropathy, and neuropathy. Although the precise molecular mechanisms underlying diabetes are not yet clear, it is widely accepted that increased levels of oxidative stress are involved in the onset, development and progression of diabetes and its related complications. In this regard, the use of natural antioxidant polyphenols, able to control free radical production, to increase intracellular antioxidant defense and to prevent the onset of oxidative stress, can be of high interest. Caffeic acid phenethyl ester (CAPE), a natural polyphenolic substance, is one of the main components of propolis. Due to its multifaceted biological activities, including antioxidant, antimicrobial, anti-inflammatory, antitumor, and immunomodulatory effects, CAPE has received great attention during the last few decades. In the present paper the therapeutic potential of CAPE in diabetes is extensively reviewed.