Among the most serious consequences of diabetes mellitus is the development of diabetic angiopathy, of which the clinical features are cardiovascular disease, retinopathy, nephropathy and neuropathy. Diabetic kidney problems affect up to one third of all patients with diabetes mellitus and are a major cause of end-stage renal failure. Although a huge number of pharmaceutical interventions are available today, diabetic angiopathy remains a leading cause of mortality and morbidity in diabetes mellitus, therefore, an urgent need exists to develop new therapeutic strategies. Recent data support the hypothesis that dysregulation of the complement system and of members of the tumor necrosis factor (TNF) superfamily may be involved in the development of diabetic vascular complications. The mannose-binding lectin pathway-an overall regulatory component of the complement system-is a particularly promising biomarker as it is directly involved in the development of diabetic angiopathy. In addition, two components of the TNF superfamily, namely TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and osteoprotegerin, may be involved in the pathogenesis of diabetic angiopathy. Several ways of specifically manipulating the complement and TNF superfamily systems already exist, but whether or not these drugs provide new targets for intervention for late diabetic complications is still to be revealed.