The scope of the present narrative review was to critically summarize the most recent experimental and clinical findings regarding the role of TRAIL in T1DM and T2DM, discuss possible underlying mechanisms for the protective role of TRAIL in T1DM and T2DM by focusing on tissue-specific effects, provide an update for the role of TRAIL in important diabetes-related complications such as ischemic heart disease and diabetic nephropathy, and highlight controversies and open questions in the field of TRAIL and metabolic disease. This evidence concerns the gene TNFSF10 and type 2 diabetes mellitus.