Autoimmune diseases (AIDs) are disorders in which the body reacts to autoantigens, leading to tissue damage. The exact pathogenesis of AIDs is still unknown. Many studies have shown that genetic factors play an important role in the occurrence and development of AIDs. In recent years, the development and application of whole-exon sequencing technology has identified several genetic variants associated with AIDs and has confirmed that these variants are involved in various disease processes through different mechanisms, including breaking immune tolerance and affecting disease severity and prognosis. This has promoted a greater understanding of AIDs. Therefore, this article reviews the application and research progress of whole-exon sequencing in patients with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren’s syndrome, and Beh?et’s disease in an effort to more clearly understand the pathogenesis of AIDs and provide new ideas for diagnosis and treatment.