Aberrant overactivation of the immune system can give rise to chronic and persistent self-attack, culminating in autoimmune disease. This is currently managed therapeutically using potent immunosuppressive and anti-inflammatory drugs. Class I phosphoinositide-3-kinases (PI3Ks) have been identified as ideal therapeutic targets for autoimmune diseases given their wide-ranging roles in immunological processes. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval with many others in development, including several intended to suppress the immune response in autoimmune and inflammatory diseases. This chapter reviews the evidence for contribution of aberrant PI3K activity to a range of autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and type I diabetes) and possible therapeutic application of isoform-specific PI3K inhibitors as immunosuppressive drugs.