Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy for which early intervention has not been shown to extend survival. However, there are many agents available that are active in this disease. Alkylating agents, the purine analogs, and monoclonal antibodies have all been shown to result in high response rates in patients with previously treated and untreated CLL. These classes of agents have been combined based on in vitro data demonstrating synergism. The purine analogs alone or in combination with alkylating agents and monoclonal antibodies result in greater response rates compared with alkylating agent-based therapy alone. However, improvement in overall survival and cure of patients with CLL has yet to be realized with these available regimens. The best initial therapy of patients with CLL remains a matter of debate.