EVs play a diverse role in the evolution of cancer, including facilitation of tumor progression and metastasis, transfer of oncogenic payloads, and stimulation of other pathophysiological processes such as angiogenesis. Oncolytic focal therapies can intervene on the tumor microenvironment (TME), and thereby EVs, in a variety of ways. Ionizing radiation, photodynamic therapy (PDT) and therapeutic ultrasound (TUS) can differentially influence EV amplitude and cargo, immunological responses, and therapeutic delivery within the TME.