Disruption of cellular communication that regulates normal physiology is often key factor in the development of disease, including cancer. Extracellular vesicles (EVs) are mediators of cell-cell communication, modulating local and distant microenvironments and playing an important role influencing tumor progression at both early and late stages. Indeed, EV-mediated communication participate in the initial steps of primary tumor transformation and proliferation, as well as the preparation of the pre-metastatic niche and subsequent metastasis. In this context, the presence of DNA in EVs (EV-DNA) is particularly intriguing, with important biological implications and significant potential as a biomarker in liquid biopsies. In this review we will discuss the mechanisms involved in EV-shed DNA and the potential impact in tumor evolution. In addition, it has become apparent in recent years that the secretion of EVs also influences the behavior of the surrounding microenvironment. An important unresolved challenge in oncology is the resistance of tumors to treatment, one of the primary causes of high cancer mortality. The role of EVs in therapy resistance has garnered considerable interest. In the later part of this review, we will also examine the potential involvement of EVs in resistance to therapy.