Intranasal drug administration provides a practical and safe way of reaching the brain parenchyma, bypassing the blood-brain barrier (BBB), within minutes. It is also an excellent strategy to deliver the drugs directly to the brain, eliminating the necessity for systemic administration, thereby reducing the potential side effects of neuroactive therapeutics. The unique connections between the brain and external environment, mediated through olfactory and trigeminal nerves, allow the direct naso-brain delivery of potent neurotherapeutics. This targeted drug delivery system has a huge potential for commercialization, as it allows an easy attainment of the effective drug dose at the target site. This chapter will be an important bunch of literature illustrating the major barriers to an effective naso-brain delivery, and the key physicochemical, biopharmaceutical, and practical considerations need attention by the researchers while formulating the efficient nose-to-brain drug delivery. © 2021 Elsevier Inc.