<p>Peripherally administered therapeutics for neurological indications are challenged with anatomical and physiological barriers that limit their ability to access their site of action in the central nervous system (CNS). This is particularly true for complex therapeutics such as antibodies, immunotherapeutics, and gene therapies. The blood–brain barrier is the specialized structure that functionally regulates the ability of blood constituents to access the CNS. Blood–brain barrier delivery technologies for protein therapeutics have been established in pre-clinical models and are beginning to be verified in clinical studies. Technologies reliant on the transcellular pathway across the blood–brain barrier utilize the receptor-mediated transcytosis mechanism. Research into the use of lipid nanoparticles (LNPs) to deliver complex therapeutics has tremendously expanded in recent years. Lipid nanoparticles represent a compelling alternative to viral vectors for the delivery of various gene therapy modalities, including messenger RNA, small interfering RNA, and antisense oligonucleotides. Functionalization of LNPs with blood–brain barrier-penetrant moieties is being explored as a means to enable CNS delivery of LNP-based therapeutics. The recent innovations and validation of LNP-based delivery systems have hastened the fulfillment of the promise of facile CNS-targeted gene therapies. This review focuses on functional aspects of the blood–brain barrier and how they relate to recent advances in LNP technologies for CNS delivery, as well as their potential impact on gene therapy.</p>