Chronic lymphocytic leukemia (CLL) is a mature lymphoid malignancy that has a variable clinical course. Recent genomic studies using next-generation sequencers have revealed recurrent genetic alterations implicated in CLL pathogenesis. Clonal evolution by stepwise acquisition of genetic mutations may result in CLL progression. Among these abnormalities, alteration of B cell receptor (BCR) signaling is critical during CLL development. In addition, signals from the microenvironment support the proliferation and survival of CLL cells. Novel molecular targeted drugs that influence these signals are now becoming clinically available.