Targeted therapy for malignant hematologic disorders has become a realistic goal with the identification of novel antibodies that are designed to act against highly expressed antigens on malignant clones. CD52 is abundantly expressed on malignant lymphocytes in chronic lymphocytic leukemia (CLL). Alemtuzumab is a humanized monoclonal antibody that targets CD52 and induces cell death by several mechanisms that are still under investigation. The initial positive results of many clinical studies that explored the activity of alemtuzumab in relapsed and/or refractory CLL have provoked many oncologists to incorporate this agent into the treatment paradigm of this disease. Prophylactic antibiotics for the duration of therapy or until patients are no longer immunocompromised are recommended. This review summarizes the clinical experience with alemtuzumab that eventually led to its approval. Recent novel prognostic factors and trends in CLL therapy are also reviewed.