Therapy for patients with chronic lymphocytic leukemia (CLL) has greatly changed over the past few years. After years of stagnation, with treatment revolving around the use of rather ineffective drugs such as alkylators, many patients are now being treated with more effective agents such as purine analogs either alone or combined with other drugs and/or monoclonal antibodies. Treatment of patients refractory to these treatments is particularly challenging and should be decided only upon a careful evaluation of the disease, patient characteristics, and prognostic factors. Refractory disease should be clearly separated from relapsing disease. The only curative therapy for patients with CLL, including those with refractory disease, is allogeneic stem cell transplantation. However, the use of allogeneic transplantation is limited because of the advanced age of most patients and the high transplant-related mortality (TRM). Transplants with nonmyeloablative regimens may reduce TRM and allow more patients to receive transplants more safely. For patients in whom an allogeneic transplantation is not feasible or in whom it is deemed inappropriate, participation in phase 2 trials should be encouraged. Finally, to investigate mechanisms to overcome resistance to therapy in CLL and to identify patients that might gain benefit from early, intensive therapies (eg, based on biologic markers) constitute a challenge that needs active investigation.