Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs. Display omitted •MSC-EV are a potential therapy through immunomodulation in multiple disease models.•Common MSC-EV mechanisms of action affect the NFκB and Stat3 pathways.•A variety of miRNA and EV-associated proteins account for foremost MSC-EV effects.•The bioengineering of MSC-EVs is a feasible option to enhance MSC-EV function.