B-cell receptor (BCR) signaling is implicated as a pivotal pathway in tumorigenesis in B-cell malignancies. The inhibitors of Bruton's tyrosine kinase (BTK) and phosphatidylinositide 3-kinase-delta (PI3K), modulating BCR signaling, have included into the clinical studies and demonstrated high response rates in B-cell lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL). The imbalance between proliferation and apoptosis is the novel target in the treatment of CLL. The newly developed targeted molecular agents such as idelalisib (CAL-101 or GS-1101), ibrutinib (PCI-32765), BCL-2 inhibitors (ABT-263 (navitoclax) and ABT-199 (venetoclax)), chimeric antigen receptors (CART19 cells), novel monoclonal antibodies, and immunomodulatory drugs try to balance between survival and programmed cell death in the pathobiology of the disease. The ongoing clinical trials focusing on the combinations of kinase inhibitors with monoclonal antibodies and other pro-apoptotic agents may lead to the chemotherapy-free protocols for the indolent incurable long disease course of B-CLL. With the greater clinical experience following more widespread use of novel molecules, the optimal combination therapies in the treatment-naive and relapsed/refractory patients will be determined, resulting in more individualized therapeutic strategies for patients with CLL.