In this review we will discuss recent progress from studies on the genetic basis of autoimmune disease and how this has advanced our understanding of the processes behind disease susceptibility and pathogenesis. We review the genetic associations with autoimmune and inflammatory disease discovered in the latest genome-wide association (GWA) scans, and discuss the importance of animal models both for generating candidates and for mechanistic studies. Investigating the natural variants of key immune regulatory molecules can give us an additional level of insight into their function and physiological regulation over gene knockouts. New data showing the association of multiple genes involved in pathogen defense highlights the potential role of infection in autoimmunity, and a more complete understanding of the pathways defective in genetically susceptible individuals will also give us a handle on how environmental and epigenetic factors may be impacting disease.