Transport of LDL (low-density lipoprotein) from plasma to arterial intima is thought to be rate limiting in the development of atherosclerosis. Its variation likely determines where lesions develop within arteries and might account for some of the currently unexplained difference in disease susceptibility between individuals. It may also be critical in the development of lipid-rich, unstable plaques. Mechanisms have been controversial but recent evidence suggests that caveolar transcytosis across endothelial cells is the dominant pathway. Receptors involved are LDLR (LDL receptor), SR-B1 (scavenger receptor class B type 1), and ALK1 (activin receptor-like kinase 1). The role of LDLR is influenced by IL-1β (interleukin-1β); the role of SR-B1 by HDL (high-density lipoprotein), DOCK4 (dedicator of cytokinesis 4), GPER (G-protein–coupled estrogen receptor), and HMGB1 (high mobility group box 1); and the role of ALK1 by BMP (bone morphogenetic protein) 9. Additionally, BMP4 stimulates transcytosis and FSTL1 (follistatin-like 1 protein) inhibits it. Fundamental transcytotic mechanisms include caveola formation, undocking, trafficking, and docking; they are influenced by cholesterol-lowering agents, MYDGF (myeloid-derived growth factor), MFSD2a (major facilitator superfamily domain containing 2a) in the blood-brain barrier, and inhibitors of dynamin-2 and tubulin polymerization. The relative merits of different therapeutic approaches are discussed, with statins, colchicine, benzimidazoles, and metformin being existing drugs that might be repurposed and salidroside and glycyrrhizic acid being nutraceuticals worth investigating. Finally, we discuss evidence against the ferry-boat model of transcytosis, the contributions of receptor-mediated, fluid-phase, and active transcytosis, and where inhibition of transcytosis might be most beneficial.