Inhibiting B cell receptor-associated kinases (BAKs) with tyrosine kinase inhibitors (TKIs) shows high efficacy in the treatment of chronic lymphocytic leukemia (CLL). The modest toxicity towards leukemic cells and their “addiction to the host” suggest the disruption of the intercellular communication within the leukemia-supporting tumor microenvironment (TME) as one of the leading mechanisms of action. To understand the effects of TKIs on the TME, tumor-derived extracellular vesicles (EVs), as crucial factors of intercellular communication, are examined. EVs carry oncogenic cargo comprising miRNA, mRNA, and tyrosine kinases, priming a leukemia-supporting niche. Here, we employ a multi-omics approach to decipher the landscape of tumor-derived EVs and assess CRISPR/Cas9-generated knockouts of BAKs to investigate the functional relevance of kinase-expressing EVs in the TME. We postulate a vital role of EVs for the action of kinase inhibition and aim to characterize CLL-EVs as novel biomarkers predicting therapy response and treatment resistance.