Chronic lymphocytic leukemia (CLL) is a heterogeneous type of malignant B cell cancer that occurs in older adults. CLL patients may stay free of cancer symptoms for a long period of time and require no treatment. However, malignant progression of CLL strikes indefinitely in some patients, and such CLL responds poorly to conventional chemotherapies and will eventually acquire chemoresistance. Currently, no efficient therapeutic options are available to prevent or stop CLL from progressing into an uncontrollable chemoresistant stage. CLL thus remains to be a challenging disease that requires research explorations for efficient therapeutic methods. CLL cells harbor gene deletions and mutations that continue to accumulate in the course of disease progression and chemotherapy. While it is difficult to directly correct genetic defects in CLL, we reviewed recent research advancements focusing on several crucial molecular pathways that support the proliferative potential of CLL. Since molecules in these pathways can contribute to proliferation, survival and chemoresistance of CLL, they are potentially useful therapeutic targets. We discussed promising methods that have been developed to target functions of these molecules. Encouraging results emerged from these continuing research efforts have provided a new hope for more efficient treatments and increased survival rates for CLL patients.