Despite the introduction of lipid-lowering drugs, antihypertensives, antiplatelet and anticoagulation therapies for primary prevention of cardiovascular and heart diseases (CVD), it remains the number one cause of death globally, raising the question for novel/further essential factors besides traditional risk factors such as cholesterol, blood pressure and coagulation. With continuous identification and characterization of non-enzymatic post-translationally modified isoforms of proteins and lipoproteins, it is becoming increasingly clear that irreversible non-enzymatic post-translational modifications (nPTMs) alter the biological functions of native proteins and lipoproteins thereby transforming innate serum components into CVD mediators. In particular renal insufficiency and metabolic imbalance are major contributors to the systemically increased concentration of reactive metabolites and thus increased frequency of nPTMs, promoting multi-morbid disease development centering around cardiovascular disease. nPTMs are significantly involved in the onset and progression of cardiovascular disease and represent a significant and novel risk factor. These insights represent potentially new avenues for risk assessment, prevention and therapy. This review chapter summarizes all forms of nPTMs found in CKD and under metabolic imbalance and discusses the biochemical connections between molecular alterations and the pathological impact on increased cardiovascular risk, novel nPTM-associated non-traditional cardiovascular risk factors, and clinical implication of nPTM in cardiovascular disease.