Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western countries. The entire pathogenesis of CLL is not clear now, but defective regulation of apoptosis seems to be more important than uncontrolled cell proliferation in CLL. There are two main pathways of apoptosis: the extrinsic pathway and the intrinsic pathway. It is worth noting that the intrinsic pathway, rather than the extrinsic pathway, appears to be the key mediator of impaired apoptosis in CLL as a result of B-cell lymphoma 2 (Bcl-2) upregulation. One subclass of pro-apoptotic members within the Bcl-2 family are Bcl-2 homology 3 (BH3)-only proteins. They can regulate directly and/or indirectly the remaining Bcl-2 proteins to endanger mitochondria and induce apoptosis. We chose three molecules from the BH3-only family, Puma, Noxa and Bim, respectively, which had shown an exciting antitumor potential in previous reports, to explore their characters and functions in tumorigenesis, therapy and drug resistance of CLL.