Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B lymphocytes in the peripheral components of the immune system. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur. In the bone marrow and secondary lymphoid tissues, the trafficking, survival, and proliferation of leukemic B cells are regulated by interactions with the microenvironment (via cell-extracellular matrix interactions, cellcell contacts, and the exchange of soluble factors) and contribute to treatment resistance. Here, we review the biology of the extracellular vesicles released into this microenvironment with cross-talk between neoplastic B cells and neighboring or remote target cells. A better understanding of the extracellular vesicles' role in CLL progression and drug resistance might open up opportunities for the development of novel therapeutics that target the pro-survival dialogue between tumor cells and the tumor microenvironment.