The term autoinflammation was initially coined to distinguish disorders characterized by recurrent episodes of inflammation in the absence of high-titer autoantibodies and antigen-specific T cells from the more common autoimmune diseases. Although this concept originally applied to monogenic hereditary recurrent fevers, it has expanded over time to include polygenic (complex) autoinflammatory diseases. Understanding of the pathogenesis of autoinflammatory diseases has grown rapidly in the past decade owing to advances in genome research and technology. Genome-wide linkage analysis, positional cloning, homozygosity mapping and candidate gene screening have led to the identification of mutations in 12 genes that are associated with monogenic diseases. Genome-wide association studies have begun to elucidate the molecular basis of complex autoinflammatory diseases. The discovery of disease-causing genetic variants has defined autoinflammation as disorder within the innate immune system, implicating IL-1 as a master cytokine, and has led to a breakthrough in therapy, with IL-1 inhibitors producing rapid and sustained amelioration of symptoms. Despite major advances, however, a substantial number of patients have no mutations in the known autoinflammatory genes. The challenge now is to find the undiscovered genes, considering that most cases are sporadic or occur within small families. New approaches and tools such as next-generation sequencing are discussed.