For decades, chemotherapy was the only available approach for patients with advanced lymphoid malignancies. Treatment paradigms were dramatically altered by the availability of novel and active targeted agents, particularly the monoclonal antibodies, alemtuzumab and rituximab. These agents are now playing an increasingly important role in the treatment of lymphoid malignancies. Alemtuzumab is being used earlier in the course of chronic lymphocytic leukemia in patients with a more intact immune system, when it is likely to have its greatest activity. The immunosuppressive properties of monoclonal antibodies are also being explored in the stem cell transplant setting, including in vivo purging and, with alemtuzumab, for the management of graft-versus-host disease. Rituximab has become ubiquitous in the treatment of most B-cell malignancies. Further research with this antibody is focused on optimizing its use and determining its role in each of the relevant disease states. In addition, newer antibodies are in development for treating chronic lymphocytic leukemia and other B-cell malignancies. New treatment regimens, including combinations of monoclonal antibodies, could enhance complete response rates and prolong progression-free survival, perhaps eventually improving our ability to cure patients with lymphoid malignancies.