Autoimmune diseases are thought to affect between 14 million and 22 million people in this country. Despite decades of research, the underlying mechanisms of disease are poorly understood, diagnosis is often difficult, and therapies that minimize systemic side effects are lacking. Major advances in our understanding of human genetic variation and remarkable new technologies are paving the way for dramatically improving our fundamental knowledge of autoimmune diseases. Gene mapping studies have clearly illustrated the complexity of these diseases, which appear to involve many genes. Very high-throughput microarray assays that can measure the expression levels of thousands of genes simultaneously are revealing important insights into key biological pathways that appear to be perturbed in autoimmune diseases. We review recent advances in genetic and genomic studies, focusing primarily on systemic lupus erythematosus and related rheumatic autoimmune diseases such as Sjögren's syndrome and rheumatoid arthritis. Identification of susceptibility genes and dysregulated biological pathways for these diseases is likely to foster development of novel diagnostic and therapeutic approaches that are increasingly tailored to the underlying pathological mechanisms.