The functional and phenotypic heterogeneity of tumor cells represents one of the greatest challenges in the successful treatment of cancer patients, because it increases the risk that certain individual tumor cells possess the ability to, for example, metastasize or to tolerate cytotoxic drugs. This heterogeneity in cellular behavior is driven by genetic and epigenetic changes and environmental differences. Recent studies suggest that an additional layer of complexity of tumor heterogeneity exists, based on the ability of cells to share functional biomolecules through local and systemic transfer of extracellular vesicles (EV), with profound effects on cellular behavior. The transfer of functional biomolecules between various populations of tumor cells and between tumor cells and nontumor cells has large consequences for both the tumor cells and the microenvironment that support the cellular behavior of tumor cells, and therefore for the clinical outcome of cancer. Here, we discuss the latest findings on EV transfer and the potential implications of EV-mediated local and systemic transmission of phenotypic behavior, particularly in the context of tumor heterogeneity, metastatic disease, and treatment response. Cancer Res; 76(8); 2071-5. ©2016 AACR.