During the last three decades a significant increase in the prevalence of autoimmune diseases was noted. More diseases apparently thought to be either genetically or environmentally induced were found to have an autoimmune origin - for example narcolepsy, depression, duodenal ulcer, etc. However, not all the autoimmune diseases fulfill Noel Rose's criteria (Shoenfeld Y, Cervera R, Gershwin M.E. Diagnostic Criteria in Autoimmune Diseases. Humana Press, Springer Science + Business Media, LLC, USA. pp 1-593, 2008). In some of the diseases, indirect criteria allude to their autoimmune etiology, i.e. the co-appearance with other autoimmune diseases, specific HLA common to autoimmunity, presence of autoantibodies, etc. The fact that narcolepsy could be induced by autoantibodies extracted from patients to mice, fulfilled N. Rose's criteria, and therefore helped to classify narcolepsy as a classical autoimmune disease. Analyzing the mechanisms by which autoimmune disease is induced, leads to a better therapies than just immunosuppression or corticosteroids. Hence the role of the new biologics, where each type is aimed in counteracting a key point in the autoinflammatory process. Unfortunately, not all the etiologies of autoimmune diseases have been revealed. Moreover there are some autoimmune diseases such as systemic sclerosis in which the pathogenetic mechanisms have not been deciphered, and therefore these conditions are still devastating and require extensive research. The aim of this article collection is to review some of the forefront issues in autoimmunity and which may lead to better diagnosis and therapies in the future.