There are several major issues related to malignancy that are of importance to the practicing clinician caring for patients with rheumatoid arthritis. Although it has been clearly established that rheumatoid arthritis is associated with an increased risk of hematologic malignancies including non-Hodgkin's lymphoma and multiple myeloma, the absolute risk of developing a hematologic malignancy is less than 1%. In rheumatoid arthritis patients with secondary Sjogren's syndrome, Felty's syndrome, or paraproteinemia, the risks for developing hematologic malignancy are likely to be even higher. These risks are balanced by reduced rates of gastrointestinal cancers. There are no conclusive data that link the FDA-approved second line therapeutic agents with the subsequent development of malignancy. However, the renal transplant experience suggests that immunosuppression alone increases the risk of subsequent malignancy. This should be a guiding principle when obtaining informed consent as well as in planning future therapeutic approaches to rheumatoid arthritis. Alkylating agents markedly increase the risk of leukemia and skin, bladder, and hematologic malignancies when used to treat rheumatoid arthritis.