Revascularization because of coronary artery disease is commonly achieved by percutaneous coronary intervention with stent deployment. Refinement in interventional techniques, major improvements in stent design (particularly drug-eluting stents), and adjunctive pharmacotherapy with dual antiplatelet regimens have led to marked reductions in the overall rates of stent failure. However, even with the advancements made in the latest generation of drug-eluting stents, unresolved biological problems persist including delayed re-endothelialization and neoatherosclerosis, which can promote late expansion of the neointima and late stent thrombosis. Novel strategies are still needed beyond what is currently available to specifically address the pathobiological processes that underpin the residual risk for adverse clinical events. This review focuses on the emerging evidence that HDL (high-density lipoproteins) and its main apo (apolipoprotein), apoA-I, exhibit multiple vascular biological functions that are associated with an improvement in stent biocompatibility. HDL/apoA-I have recently been shown to inhibit in-stent restenosis in animal models of stenting and suppress smooth muscle cell proliferation in in vitro studies. Reconstituted HDL also promotes endothelial cell migration, endothelial progenitor cell mobilization, and re-endothelialization. Furthermore, reconstituted HDL decreases platelet activation and HDL cholesterol is inversely associated with the risk of thrombosis. Finally, reconstituted HDL/apoA-I suppresses key inflammatory mechanisms that initiate in-stent neoatherosclerosis and can efflux cholesterol from plaque macrophages, an important function of HDLs that prevents plaque progression. These unique multifunctional effects of HDL/apoA-I suggest that, if translated appropriately, have the potential to improve stent biocompatibility. This may provide an alternate and more efficacious therapeutic pathway for the translation of HDL.