A dramatic change has occurred in the management of chronic lymphocytic leukemia (CLL) over the past 20 years. The use of newer therapies, including the purine analogues, has resulted in higher frequencies of response. Combination therapy with purine analogues, alkylators, and/or monoclonal antibodies represents a promising new approach to the treatment of patients with CLL. The most commonly studied regimens have utilized fludarabine, but severe myelosuppression and immunosuppression of these combinations require close attention to dosing and schedule. Of the purine analogues that show activity in CLL, pentostatin appears to be the least myelosuppressive. These combination strategies are associated with high-quality responses in the majority of patients and may one day lead to improved survival or possibly even a cure for patients with CLL.