Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches.