An enhanced understanding of the important pathways governing chronic lymphocytic leukemia (CLL) cell survival and the critical role played by the microenvironment in the pathogenesis of the disease has brought new opportunities for drug development in CLL. Several new targets have been identified, and novel agents are under intense investigation in clinical trials. Some of these agents are already demonstrating promising anti-CLL activity on their own, whereas others hold promise in combination with existing therapeutic options. As the use of monoclonal antibodies for chemoimmunotherapy becomes standard clinical practice, the future holds promise for concurrent targeting of the tumor cell as well as its microenvironment.