Pressures of life on Earth experienced by our ancestors – as multicellular beings, as hosts to parasites, and as home to microbes – shaped the evolved structure and function of our immune systems.  Some of the traits favored by natural selection have conferred resistance against infections while opening vulnerabilities to autoimmune diseases.  I will illustrate why analysis of the deep-time origins of mammalian immune systems reveals general principles of optimal defense and helps to explain why hosts are so profoundly variable in their susceptibility to infectious and inflammatory diseases. (#40692)