The main and most critical function of the immune system is to distinguish between self and non-self and react accordingly. Differentiating self-reactive immune cells as soon as they develop is the phenomenon of tolerance against self-antigens and is a highly regulated process. The development of autoantibodies is a sign of the breakdown of tolerance and may be the harbinger of the onset of an autoimmune disease. It is well-known fact that many systemic autoimmune diseases (AUIDs) first manifest in the oral cavity. If proven that oral infections trigger AUIDs, then improving oral health may be a potential therapeutic strategy to reduce autoimmune disease incidence. Although etiology and pathogenesis of specific AUIDs may vary, presentation in the oral cavity often involves oral lesions manifested at early stages of systemic inflammatory and autoimmune disease. Therefore regular dental and medical checkups may provide an opportunity for clinicians, in particular dentists, to contribute to earlier detection of AUIDs thereby improving long-term treatment options and overall patient prognosis. Mechanisms leading to the onset of autoimmune disease are still being considered. Epidemiological inquires and the increasing numbers of genome-wide association studies have analyzed the breakdown of tolerance and the causes behind autoimmunity. The role of the environment is crucial in the onset of autoimmunity via the breakdown of tolerance; through toll-like receptors that mediate innate immunity which in turn triggers the adaptive autoimmune response, T regulatory cells and Th17 differentiation, through changes in the spleen autoantibody production due to a change in the B cell count, and through self antigen and epigenetic deviations induced by environmental spurs. In spite of many research efforts and the accumulation of innovative data, there are still multiple gaps in knowledge pertaining to this subject matter. The autoimmune process begins with the activation of Tcells by antigen presenting cells (APC) and progresses to CD4+ CD25+ Tcells and forkhead box P3 (Foxp3), which stimulate Th1 and Th2 responses and finally B cell activation, which plays a role in autoimmune development. This paper will review the etiopathogenesis of autoimmune diseases and different cell players as well as transcription factors such as TGF–β, IL–6, IL–10, IL–17, Th–17, T reg cells, B reg cells, Th–1, Th–2, and INF–γ. This paper aims to review published evidence and further explore the etiopathology of individual autoimmune diseases such as Behcet's, Crohn's disease, Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis and the subsequent dental implications and therapeutic management. This review also aims to study the most relevant autoimmune, auto-inflammatory, and systemic chronic inflammatory diseases, as well as mechanisms of autoimmune manifestation with respect to oral health.