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The blood-brain barrier is a dynamic multicellular interface that regulates the transport of molecules between the blood circulation and the brain parenchyma. Proteins and peptides required for brain homeostasis cross the blood-brain barrier via transcellular transport, but the mechanisms that control this pathway are not well characterized. Here, we highlight recent studies on intracellular transport and transcytosis across the blood-brain barrier. Endothelial cells at the blood-brain barrier possess an intricate endosomal network that allows sorting to diverse cellular destinations. Internalization from the plasma membrane, endosomal sorting, and exocytosis all contribute to the regulation of transcytosis. Transmembrane receptors and blood-borne proteins utilize different pathways and mechanisms for transport across brain endothelial cells. Alterations to intracellular transport in brain endothelial cells during diseases of the central nervous system contribute to blood-brain barrier disruption and disease progression. Harnessing the intracellular sorting mechanisms at the blood-brain barrier can help improve delivery of biotherapeutics to the brain.