The ubiquitin system is an evolutionarily conserved and universal means of protein modification that regulates many essential cellular processes. Endothelial dysfunction plays a critical role in the pathophysiology of sepsis and organ failure. However, the mechanisms underlying the ubiquitination-mediated regulation on endothelial dysfunction are not fully understood.Here we review the advances in basic and clinical research for relevant papers in PubMed database. We attempt to provide an updated overview of diverse ubiquitination events in endothelial cells, discussing the fundamental role of ubiquitination mediated regulations involving in endothelial dysfunction to provide potential therapeutic targets for sepsis.The central event underlying sepsis syndrome is the overwhelming host inflammatory response to the pathogen infection, leading to endothelial dysfunction. As the key components of the ubiquitin system, E3 ligases are at the center stage of the battle between host and microbial pathogens. Such a variety of ubiquitination regulates a multitude of cellular regulatory processes, including signal transduction, autophagy, inflammasome activation, redox reaction and immune response and so forth. In this review, we discuss the many mechanisms of ubiquitination-mediated regulation with a focus on those that modulate endothelial function to provide potential therapeutic targets for the management of sepsis.