Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthritis that can lead to significant damage and dysfunction of involved joints. Prior to 1998, treatment options were limited to disease modifying anti-rheumatic drugs, commonly referred to as DMARDs like methotrexate, sulfasalazine, hydroxychloroquine, and gold salts. Tumor necrosis factor alpha (TNF-α) is a central cytokine that drives the inflammation in RA; hence inhibition of TNF-α offers an attractive treatment strategy in RA. The introduction of TNF-α inhibitors, a class of biologic DMARDs, has dramatically changed the treatment of RA as these are highly effective therapies. Medication-related adverse events remain a major problem in health care. This is true of the TNF-α antagonists as well, with particular concerns about increased risks of infections and malignancy. Because clinical trials performed prior to medication approval are limited by the number and clinical complexity of participants and the duration of the trials, post-marketing surveillance is critical in identifying adverse events. In order to better clarify the safety issues related to the use of TNF-α inhibitors in RA, several studies using large observational registries along with pooled meta-analyses of these studies have been published. This review will summarize the data from these recent studies on the question of malignancy risk associated with TNF-α inhibitor use in RA. It is comforting that the data from these studies do not support an increased risk of cancer, except non-melanoma skin cancer, with the use of TNF-α antagonists in adults with RA.