Galectin-3 is a versatile molecule which exerts several and sometimes opposite functions in various pathophysiological processes. Recently, galectin-3 has gained attention as a powerful predictor of heart failure and mortality, thus becoming a useful prognostic marker in clinical practice. Moreover, though not specifically investigated in diabetic cohorts, plasma levels of galectin-3 correlated with the prevalence of diabetes and related metabolic conditions, thus suggesting that pharmacological blockade of this lectin might be successful for treating heart failure especially in subjects suffering from these disorders. Indeed, galectin-3 is considered not only as a marker of heart failure, but also as a mediator of the disease, due to its pro-fibrotic action, though evidence comes mainly from studies in galectin-3 deficient mice. However, these studies have provided contrasting results, with either attenuation or acceleration of organ fibrosis and inflammation, depending on the experimental setting and particularly on the levels of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs), of which galectin-3 is a scavenging receptor. In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function of this lectin. Conversely, in experimental models of acute inflammation and fibrosis, galectin-3 deficiency resulted in attenuation of tissue injury. There is a need for prospective studies in diabetic patients specifically investigating the relation of galectin-3 levels with complications and for further animal studies in order to establish the effective role of this lectin in organ damage before considering its pharmacological blockade in the clinical setting.