Chronic kidney disease (CKD) is characterized by a gradual endogenous intoxication caused by the progressive accumulation of bioactive compounds that in normal conditions would be excreted and/or metabolized by the kidney. Uremic toxicity now is understood as one of the potential causes for the excess of cardiovascular disease and mortality observed in CKD. An important family of uremic toxins is that of the peptidic middle molecules, with a molecular weight ranging between 500 and 60,000 Da, which makes them, as a consequence, difficult to remove in the process of dialysis unless the dialyzer pore size is large enough. This review provides an overview of the main and best-characterized peptidic middle molecules and their role as potential culprits of the cardiometabolic complications inherent to CKD patients.