The present review gives an overview of the known and newly detected middle molecules and their biological potential. Since many middle molecules were shown to affect leukocyte, endothelial cell, smooth muscle cell and/or thrombocyte function, the likelihood of their role in cardiovascular damage related to renal failure is described. In addition, the middle-molecule behaviour during dialysis is commented. The impact of dialytic removal by diffusion or convection in clinical studies is extensively discussed reflecting the benefit on patient survival and/or clinical outcome. The continuing search for new culprits will result in therapeutic options including improved removal of uremic solutes and/or the search for pharmacological strategies blocking responsible pathophysiological pathways.