Chalcones are a group of plant-derived polyphenolic compounds that possess a wide variety of biological activities. Several lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. The beneficial effect of these substances has been studied in relation to diabetes mellitus. Several studies have demonstrated that chalcones either from natural or synthetic sources can influence carbohydrate pathways, especially glucose metabolism. These studies verified the effectiveness of chalcones as antihyperglycemic and/or hypoglycemic agents through in vitro and in vivo experimental responses. In this context, these molecules are attractive substances which can enrich the current therapy options and they have become the subject of considerable interest in both academia and industry. The purpose of this review is to discuss the recent developments related to the chemistry and medicinal properties of chalcones, especially concerning their role in glucose homeostasis and carbohydrate metabolism. Also, taking into account the relevant structure–activity relationships of these compounds, the development of new approaches to study the interactions of chalcones in specific targets combining in silico (computational modeling) and in vitro pharmacological studies on β-cells represents a challenge for future perspectives aimed at characterizing molecular targets for diabetes therapy.