High-density lipoprotein (HDL) is cardioprotective because of its anti-atherogenic properties. Nevertheless, our goal to optimize HDL cholesterol (HDL-C) levels have had little effects on the atherothrombotic burden and suggests a closer look be taken at HDL function and dysfunction. HDL is a group of complex macromolecules composed of a lipid- and proteome that work in synergy to execute its anti-inflammatory, anti-atherogenic, and anti-thrombotic effects. However, throughout its life-span in circulation, HDL undergoes significant modification. Carbamylation, a non-enzymatic and irreversible post-translational modification of protein, is one effector of HDL which has growing evidence that it plays a crucial role in the development and progression of atherosclerotic cardiovascular disease (ASCVD), particularly in chronic kidney disease (CKD). We summarize HDL’s function, susceptibility to modification, and discuss HDL carbamylation and its effect in cardiovascular disease.