Lipoproteins are spherical particles comprised of lipid and protein constituents that function in circulating exogenous and endogenous lipids via the bloodstream to cells and tissues. The protein components of lipoprotein particles include enzymes and transport factors involved in lipid metabolism, and apolipoproteins that serve as ligands for cell surface receptors, cofactors for enzymes, and stabilisation factors for maintaining lipoprotein structure. There are at least 15 different apolipoproteins that have been characterized to date, including apolipoprotein C-I (apoC-I). Mature apoC-I is comprised of 57 amino acids with a molecular weight of 6.6 kDa and forms a helix-turn-helix structure in the presence of lipid. This small apolipoprotein plays several roles in lipoprotein metabolism as a component of chylomicrons, very low density lipoproteins (VLDL) and high density lipoproteins (HDL). In this review, we describe the structure and function of lipoproteins; the roles of the exogenous, endogenous, and reverse cholesterol transport pathways; model lipid systems for characterising apolipoprotein-lipid interactions, and feature the structure, biomolecular interactions, and important functions of human apoC-I in health and disease.