Five anti-TNF agents, infliximab, adalimumab, etanercept, golimumab and certolizumab pegol are approved worldwide for the treatment of RA. Anti-TNF agents, bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). Differences on affinity and avidity for soluble and transmembrane TNF-alpha were showed. Different activity on cells apoptosis, complement-dependent cytotoxicity (CDC) antibody dependent cell-mediated cytotoxicity (ACDC) were described. Some dramatic changes in gene expression were seen with all the anti-TNFs. Reviewing the biology of transmembrane TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.