Despite the significant advantages in clinical practice associated with TNF-inhibitors, a loss of response over time is sometimes observed, in some cases possibly due to immunogenicity, i.e. the development of antibodies direct against the drug. This review evaluates the immunogenicity of different anti-TNF agents, and discusses its effects on efficacy and safety. Available evidence indicates that all anti-TNF drugs may induce an immune response. However, the variation in the occurrence of anti-drug antibodies, as well as the variation in the impact of antibodies on the efficacy and safety, can be explained by drug conformation itself, use of concomitant immunosuppressants and differences in dosing regimen and route of administration. The association between the development of anti-drug antibodies and low drug serum concentrations is clinically relevant since it is likely related to low response. Strict monitoring of neutralising antibodies might be useful for tailoring therapeutic strategy. There is no evidence of cross-reactivity among different drugs: immunogenicity (the development of specific anti-drug antibodies to one TNF inhibitor) does not seem to affect the effectiveness of another anti-TNF agents; therefore, switching to another drug of the same class might be effective in patients who have developed anti-drug antibodies to a TNF inhibitor.