Currently, five anti-TNF biologic agents are approved for the treatment of rheumatoid arthritis (RA): adalimumab, infliximab, etanercept, golimumab and certolizumab pegol. Formation of anti-drug antibodies (ADA) has been associated with all five agents. In the case of adalimumab and infliximab, immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response, but for the other three agents, data on immunogenicity are scarce, suggesting that further research would be valuable. Low ADA levels might not influence the efficacy of anti-TNF therapy, whereas high ADA levels impair treatment efficacy by considerably reducing unbound drug levels. Immunogenicity is not only an issue in patients treated with anti-TNF biologic agents; the immunogenicity of other therapeutic proteins, such as factor VIII and interferons, is well known and has been investigated for many years. The results of such studies suggest that investigations to determine the optimal treatment regimen (drug dosing, treatment schedule and co-medication) required to minimize the likelihood of ADA formation might be an effective and practical way to deal with the immunogenicity of anti-TNF biologic agents for RA.