Non-Hodgkin lymphoma is a diverse group of lymphoid malignancies treated historically with cytotoxic chemotherapy. Recent technologic advances have enabled the development of new therapies specifically targeted to inhibit various pathways involved in disease pathophysiology. Led by the anti-CD20 monoclonal antibody rituximab, these agents are expected to revolutionize patient care. Several new drugs might have limited single-agent activity but could combine with other targeted therapies to produce significant effects. Although the current level of understanding makes this sort of rational combination challenging, there is evidence that certain combinations might be very effective. Examples include the combination of rituximab with other monoclonal antibodies, immunomodulatory drugs, Bcl-2 inhibitors, and bortezomib. All of these agents face the challenge of optimal integration with rituximab. The strategies most likely to produce initial success will be those that incorporate rituximab in sensitive patients, as well as those that target patient populations with rituximab-refractory disease. Ideally, these studies will incorporate biologic correlates, such that the mechanisms of action and the patients most likely to benefit can be better defined. We discuss several combinations, their rationale, and the clinical evidence that justifies further evaluation.