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Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.T., B.S.S., R.R., T.T. and N.J.H. are listed as inventors in patent applications filed by Johns Hopkins Technology Ventures covering novel compositions of nSMase2 inhibitors and their utility., (Copyright © 2021 Elsevier Ltd. All rights reserved.)