Nanocrystals (NCs) have emerged as a promising strategy for enhancing drug delivery through mucosal routes, addressing the inherent challenges posed by mucosal barriers in various systems such as the gastrointestinal, respiratory, genitourinary, and ocular tracts. These barriers, characterized by a protective mucus layer, enzymatic degradation, limited permeability, and rapid clearance mechanisms, often hinder the effective absorption and therapeutic efficacy of drugs. By leveraging the unique properties of nanotechnology, NCs can significantly improve drug stability and bioavailability, allowing for targeted and sustained release at the site of action. Furthermore, strategies for decorating nanocarriers include both mucoadhesive coatings, which facilitate adhesion to the mucus layer, and mucopenetrative coatings, such as PEGylation, which enable deeper penetration and prolonged retention in mucosal tissues. Overall, ongoing advancements in NCs technology hold great promise for overcoming the barriers of mucosal drug delivery, potentially leading to more effective therapeutic interventions for a wide range of diseases. This chapter primarily focuses on introducing the various mucosal barriers of the human body, as well as the challenges they present and the treatments that have been developed. Special attention is given to nanocrystals as a drug delivery system and their role in therapeutic applications.