Immune checkpoint inhibitor (ICI) therapy is now in widespread clinical use for the treatment of lung cancer. Although patients with autoimmune disease and other comorbidities were excluded from initial clinical trials, emerging real-world experience suggests that these promising treatments may be administered safely to individuals with inactive low-risk autoimmune disease such as rheumatoid arthritis or psoriasis, mild to moderate renal and hepatic dysfunction, and certain chronic viral infections. Considerations for ICI in autoimmune disease populations include exacerbations of the underlying autoimmune disease, increased risk of ICI-induced immune-related adverse events, and potential for compromised efficacy if patients are receiving chronic immunosuppression. Immune checkpoint inhibitor use in higher-risk autoimmune conditions, such as myasthenia gravis or multiple sclerosis, requires careful evaluation on a case-by-case basis. Immune checkpoint inhibitor use in individuals with solid organ transplant carries a substantial risk of organ rejection. Ongoing research into the prediction of ICI efficacy and toxicity may help in patient selection, treatment, and monitoring.