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Inflammatory processes arising from metabolic abnormalities are known to precipitate the development of CVD. Several metabolic and inflammatory markers have been proposed for predicting the progression of CVD, including high density lipoprotein cholesterol (HDL\u2010C). For ~50\u00a0years, HDL\u2010C has been considered as the atheroprotective \u2018good\u2019 cholesterol because of its strong inverse association with the progression of CVD. Thus, interventions to increase the concentration of HDL\u2010C have been successfully tested in animals; however, clinical trials were unable to confirm the cardiovascular benefits of pharmaceutical interventions aimed at increasing HDL\u2010C levels. Based on these data, the significance of HDL\u2010C in the prevention of CVD has been called into question. Fundamental <jats:italic>in vitro<\/jats:italic> and animal studies suggest that HDL\u2010C functionality, rather than HDL\u2010C concentration, is important for the CVD\u2010preventive qualities of HDL\u2010C. Our current review of the literature positively demonstrates the negative impact of systemic and tissue (i.e. adipose tissue) inflammation in the healthy metabolism and function of HDL\u2010C. Our survey indicates that HDL\u2010C may be a good marker of adipose tissue health, independently of its atheroprotective associations. We summarize the current findings on the use of anti\u2010inflammatory drugs to either prevent HDL\u2010C clearance or improve the function and production of HDL\u2010C particles. It is evident that the therapeutic agents currently available may not provide the optimal strategy for altering HDL\u2010C metabolism and function, and thus, further research is required to supplement this mechanistic approach for preventing the progression of CVD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. 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