OBJECTIVE Powerful new methods are allowing identification of genetic risk factors in large populations of adults with autoimmune diseases. In this review, we describe the advantages and limitations of genetic methodologies, and how these methods have been used to discover candidate genes in smaller populations of pediatric patients. We also introduce novel concepts for nontraditional modes of genetic inheritance that may be important in the pathogenesis of autoimmunity. RESULTS Candidate genes identified by linkage analyses and genome-wide association scans in adult populations have led to focused genetic studies in pediatric populations. Some genes are associated with subsets of both adult and pediatric patients; others appear to be age specific. Novel concepts in genetics have uncovered potential contributions of maternal compared with paternal transmission, noninherited maternal alleles that may work through maternal microchimerism, and sex-specific epigenetic mechanisms of immunoregulation. CONCLUSIONS Advancing methods are leading to the discovery of genes associated with childhood autoimmune diseases. However, the genetic contribution to disease risk for any one gene remains less than 30% for most diseases, suggesting that pediatric autoimmunity is not primarily genetic in a classical sense. A combinatorial approach considering the contributions of multiple genes, mode of inheritance, and environmental influences will be required to fully understand the mechanisms of pathogenesis in pediatric autoimmune disease.