Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of cancer, mainly in the context of chronic inflammation. Recent publications, however, have reported an increased risk of lymphoma in rheumatoid arthritis patients treated with immunomodulatory TNF-α blockers. To assess the role of TNF-α in neoplasia, a review of TNF-α effects on experimental and human cancer and the influence of anti-TNF-α therapy on cancer development was conducted. TNF-α produces a variety of cellular responses which, with sustained increased levels of activity, could either facilitate or inhibit tumorigenesis. In experimental models, most evidence supports the potential enhancement of neoplasia by TNF-α. The increased frequency of lymphoma that has been reported in patients with rheumatoid arthritis treated with anti-TNF-α therapy may reflect the severity of the disease, which could be associated with greater TNF-α activity. Skin cancer is also reported to be increased in some studies. Other findings, to the contrary, suggest that TNF-α inhibition could impede tumorigenesis. It is concluded that the presently available data do not permit a robust conclusion on the potential effects of anti-TNF-α therapy on the risk of human neoplasia, but reduction in neoplasia seems probable. Further investigation of this important topic is clearly warranted.