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Access challenges include physical barriers such as the blood\u2013brain barrier, technical barriers such as procedural considerations, and variability in response to biological therapies that are dependent on route of delivery. In this review, these challenges are discussed along with the practicalities of therapeutic access for biological therapies to the CNS by systemic intravenous (IV) delivery, intrathecal delivery, and direct intraparenchymal delivery in the context of epilepsy and with relevance to other neurological disorders. In the context of IV delivery, the practicalities of CNS target and off-target systemic effects are discussed. In the context of intrathecal delivery, the practicalities of procedural access, cerebrospinal fluid dynamics, and tissue penetrance are reviewed. Finally, in the context of direct intraparenchymal delivery, the technical aspects of therapy administration, local and systemic spread, and immune response are highlighted. Each delivery method provides a different balance of procedural, targeting, and inflammatory considerations, which may affect future therapeutic agent selection and trial design. 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