Autoimmune diseases affect about 3% of the world population, more frequently women than men, and their incidence is attributed to an immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate immuno-regulatory mechanisms. Advances in understanding the cellular activity pathways and cytokine expression profiles have led to new therapeutic regiments, like soluble receptors, monoclonal antibodies and molecular mimetics that have been employed to enhance or replace conventional immunosuppressive therapies. Among new biologicals that have been developed to target defined pathways of the adaptive immune response are TNF-α inhibitors. TNF-α is a proinflammatory cytokine elevated in many autoimmune lesions, and its deregulation characterizes many autoimmune diseases. TNF-α seems to exhibit an immunoregulatory role that can alter the balance of T regulatory cells and orchestrate acute immunological responses. More than half a million autoimmune patients have received therapy with anti-TNF-α antibodies, usually because they were refractory to conventional treatments. This review offers an update on TNF-α-targeted therapies used in patients suffering from various autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on the efficacy and safety that clinical trials have shown until now.