TNF-α inhibitor (TNFi) therapies have transformed the treatment of several rheumatic musculoskeletal diseases. However, the majority of TNFi's are immunogenic and consequent anti-drug antibodies formation can impact on both treatment efficacy and safety. Several controversies exist in the area of immunogenicity of TNFis and drug safety. While anti-drug antibodies to TNFis have been described in association with infusion reactions; serious adverse events (AEs) such as thromboembolic events, lupus-like syndrome, paradoxical AEs, for example, vasculitis-like events and other autoimmune manifestations have also been reported. The expansion of the biologic armamentarium, new treatment strategies such as introduction/switching to biosimilars and cost-saving approaches such as TNFi tapering, may all have a potential impact on immunogenicity and clinical sequelae. In this review we evaluate how evolution of biologics relates to drug safety and immunogenicity, appraise relevant evidence from trials, spontaneous pharmacovigilance and observational studies and outline the areas of uncertainty that still exist.