AbstractExtracellular vesicles (EVs) are promising next‐generation therapeutics and drug delivery systems due to demonstrated safety and efficacy in preclinical models and early‐stage clinical trials. There is an urgent need to address the immunogenicity of EVs (beyond the apparent lack of immunotoxicity) to advance clinical development. To date, few studies have assessed unintended immunological recognition of EVs. An in‐depth understanding of EV‐induced immunogenicity and clearance is necessary to develop effective therapeutic strategies, including approaches to mitigate immunological recognition when undesired. This article summarizes various factors involved in the potential immunogenicity of EVs and strategies to reduce immunological recognition for improved therapeutic benefit.