Lymphoproliferative disorders are characterized by the abnormal accumulation of aberrant lymphocytes, which frequently interfere with the processes associated with immunologic response and hematopoiesis. Chronic lymphocytic leukemia (CLL) has traditionally been considered indolent, with a prolonged clinical course. However, a large proportion of patients with CLL have severe symptoms, a poor prognosis, and often require more immediate treatment of their leukemia. Over the last 5 years, technology has transformed the approach to treating patients with CLL. Molecular markers are now available that characterize patients with poor-risk disease who may benefit from earlier or more aggressive therapeutic intervention. Biological markers have also been identified that assist in predicting responses to specific agents and may help select an effective therapeutic approach. The advent of more targeted monoclonal antibody therapies, used in combination with chemotherapy regimens or as monotherapy, has the potential to eradicate disease to a point of undetectability by the most sensitive tests available, thereby possibly extending the goal of therapy to include a cure. Because recent data have shown that achieving minimal residual disease (MRD) in the bone marrow is one of the most important factors in predicting duration of remission, MRD may be an appropriate therapeutic end point for patients with poor-risk CLL. The use of rituximab with the cytotoxic agents cyclophosphamide and fludarabine has achieved complete remission with no detectable CLL, as assessed by MRD techniques in a significant proportion of previously untreated and previously treated CLL patients. Monotherapy with alemtuzumab has also been shown to achieve a complete response with undetectable MRD in patients with relapsed/refractory disease. This article reviews recent advances in identifying patients who have poor-risk disease and explores the potential importance of MRD status as an outcome measure of CLL therapy.