PURPOSE OF REVIEW: Despite ongoing efforts to decipher the cancer genome, 
discoveries of new targetable genetic lesions within cancer cells are rare. 
Therefore, alternative approaches are needed. Signals from the microenvironment 
are increasingly recognized as drivers of disease progression in hematologic and 
solid cancers. Consequently, there is growing interest in targeting the 
tumor-microenvironment cross-talk. This review highlights recent therapeutic 
advances in targeting the microenvironment in chronic lymphocytic leukemia 
(CLL).
RECENT FINDINGS: CLL is the poster child for microenvironment-dependent 
malignancies, because the clonal CLL B cells are highly dependent on external 
signals for maintenance and expansion. These pathways recapitulate those 
responsible for normal B-cell expansion in germinal centers. The most prominent, 
conserved mechanism is B-cell receptor (BCR) signaling, which promotes CLL cell 
survival and expansion in lymphatic tissue areas designated proliferation 
centers. BCR signaling now can be targeted by new targeted kinase inhibitors.
SUMMARY: Small molecule inhibitors of BCR signaling kinases, Bruton's tyrosine 
kinase (Btk) inhibitor ibrutinib and the phosphoinositide 3'-kinase delta 
(PI3Kδ) inhibitor GS-1101, are currently transforming the landscape of CLL 
therapy. This development exemplifies that the microenvironment has become a 
lively successful area of translational research.