Crohn's disease is a complex multifactorial disorder characterized by the alternation of a cytokine-driven T-lymphocyte-depending inflammation of the intestinal mucosa, and "off" periods, where patients are completely asymptomatic. Although all the causative factors have not been clearly identified, the continuously growing understanding of the major abnormalities of the inflammatory and immune response leading to the often debilitating symptoms reported by Crohn's disease patients, improves our capacity to characterize new potential therapeutic targets with the subsequent hope to discover new (more efficient and less toxic) drugs. Saying that, in the recent years, tumor necrosis factor-alpha undoubtedly emerges as a key cytokine involved in Crohn's disease pathogenesis, and constant efforts have been made to control tumor necrosis factor-alpha deleterious effects in Crohn's disease. This review schematically summarizes the current understanding of tumor necrosis factor-alpha's role in Crohn's disease pathogenesis as well as the present and the future treatment strategies which may be helpful in patients by inhibiting tumor necrosis factor-alpha production and effects. Beside drugs under investigation, several original approaches are described or mentioned, most of them leading to recent patents such as polyclonal anti-TNF-alpha antibodies from avian origin, allowing potentially oral administration, or combination strategies such as vitamin D and anti-TNF-alpha antibodies or methotrexate and anti-TNF-alpha antibodies, or decoy oligodeoxynucleotides interfering with the binding of nuclear factor-kappaB to its target genes promoters.