Despite significant advancements in the treatment of cancer, therapeutic resistance remains a major hurdle for the achievement of full cures. Besides being typically driven by intratumoral heterogeneity, such acquired resistance also relies heavily on cell-cell communication whereby extracellular vesicles (EVs) carrying resistance-related components can be transferred from drug-resistant cells or nontumorigenic members within tumor microenvironment (TME) to their sensitive neighbors. The cargo and membrane surface proteins of EVs derived from drug-resistant cells and TME cells carry abundant biological information, transferring therapy-resistant capacity to sensitive cancer cells. Hence, a deep understanding of the roles of EVs in cancer therapy resistance will facilitate identifying biomarkers and developing new approaches to restore therapy sensitivity. In this review, we summarize our current understanding regarding the causes and effects of EV-mediated cell-cell communication in drug resistance, with a particular notice on how various kinds of cargoes derived from different cells within TME are linked to the resistant phenotype. We also discuss how this knowledge can contribute to improvements in clinical practice, that is, the opportunities and challenges of EVs in functioning as potential biomarkers in predicting therapeutic resistance and, by extension, EV-based therapy in achieving deeper and longer-lasting clinical responses.