Analysis of the number of genes involved in the regulation of the expression of SAT in OS, by means of crosses with the unrelated inbred CB line, gave the following results: 1) The production of Tg-AAb is regulated by one or two genes; 2) the sensitivity of the thyroid to autoimmune attack is under the control of about 3 genes; 3) the expression of SAT, as measured by mononuclear cell infiltration of the thyroid gland, is thus encoded by at least 4-5 genes (approximately 2 of which regulate the immune system hyperreactivity against antigens of the thyroid, and 3 of which regulate the sensitivity of the target organ to an attack by the immune system. It should, however, not be forgotten that this calculation, which results in 5 genes as being crucial for the development of SAT, is only valid for the combination of the OS and the CB inbred line. A different number might have arisen with the use of a different inbred line for crossing experiments. 4) The genes involved in the genetic control of SAT can be divided into two categories, major and minor genes. One family of major genes regulates the hyperreactivity of the immune system and perhaps its specificity for thyroid antigens. A second family of major genes encodes the target organ susceptibility to the attack of the immune system. The minor genes modulate the expression of the major genes and are especially important in animals with an incomplete set of major genes. The influence of sex hormones and the MHC are examples of such genes. MHC genes play an important role in outbred populations, but they are not a prerequisite for the development of the disease. Fully developed, early onset SAT is only seen in an animal where all major genes are present. The existence of two-gene families, each composed of relatively few genes, might guarantee to a species that SAT will not be too frequent in outbred populations.