This chapter provides a comprehensive overview of the relationship between immune checkpoints and autoimmune diseases. It begins by introducing the concept of autoimmunity and the role of central and peripheral tolerance in preventing inflammatory and autoimmune diseases. It then explores the involvement of various immune checkpoints, particularly CTLA-4, PD-1, and TIM-3, in different autoimmune disorders. The chapter covers several key autoimmune conditions, including rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren’s syndrome, and systemic sclerosis. It also explores multiple sclerosis as a central nervous system autoimmune disease, autoimmune thyroid diseases, psoriasis, and type 1 diabetes. For each condition, the chapter discusses the association of immune checkpoint gene polymorphisms with disease susceptibility, the expression patterns of checkpoint molecules on immune cells, and their potential role in disease pathogenesis and progression. It highlights how alterations in immune checkpoint expression or function can contribute to the breakdown of self-tolerance and the development of autoimmunity. It also examines the complex interplay between different checkpoint molecules and their impact on various immune cell populations, particularly T cells. The chapter also describes the potential of targeting immune checkpoints for therapeutic purposes in autoimmune diseases to draw parallels with their use in cancer immunotherapy. Throughout the chapter, it emphasizes the dual nature of immune checkpoints in maintaining immune homeostasis and their potential involvement in both protective and pathogenic processes in autoimmune conditions.