Type 1 diabetes (T1D) and type 2 diabetes (T2D) are two distinct diseases, with different etiology and pathogenesis, but with a common outcome (hyperglycemia), caused by almost complete or reduced loss of β-cell functional mass, respectively. Although the causes that lead to β-cell failure are different (typically immune-mediated for T1D, while related to metabolic stress for T2D), the underlying molecular pathways are almost similar in both forms of diabetes. In this review we try to highlight common molecular mechanisms of β-cells damage in T1D and T2D, which could suggest new promising common therapeutic targets.