Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation,permeability,and cell death.Disruption of cell junctions is implicated in a variety of human disorders,such as inflammatory diseases and cancers.Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases.Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability,receptor intalization,enzyme activity,and protein-protein interactions.Ubiquitination is tightly regulated by ubiquitin E3 ligases and can be reversed by deubiquitinating enzymes.Recent studies have been focusing on investigating the effect of protein stability in the regulation of cell-cell junctions.Ubiquitination and degradation of cadherins,claudins,and their interacting proteins are implicated in epithelial and endothelial barrier disruption.Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases’ biological activities.Taken together these studies,ubiquitination plays a critical role in modulating cell junctions and motility.In this review,we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions,including junction proteins,their interacting proteins,and small Rho GTPases.We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiqultination on human disorders caused by dysfunction of cell junctions.