The lipidome and proteome of HDL in normolipidemic, normoglycemic healthy subjects are integral to expression of the optimal biological activities of HDL particles which are equated with its functionality. The lipidome and proteome are however markedly altered in both type 1 diabetes and type 2 diabetes, leading to functional impairment, that is, dysfunctionality. The lipidome is composed of more than 400 molecular lipid species (PJ Meikle and MJ Chapman, unpublished observations) while the proteome is composed of at least 95 distinct protein species. Multiple distinct particle subfractions are now recognised with the circulating HDL pool, which now extends to distinct particle subspecies with defined protein and lipid components. Lipid–lipid, lipid–protein and protein–protein interactions ensure the integrity and stability of HDL particles; such interactions may confer conformational changes in major apolipoproteins such as apo-AI and apo-AII, which may in turn impact functionality. The lipidome, proteome and functionality of HDL are impacted by their metabolic environment, major factors including dyslipidaemia and dysglycaemia.