RESEARCH on the cause of autoimmune thyroid disease (AITD) has in the past focused on potentially unique and specific abnormalities that could provide a unitary explanation for these illnesses [Graves' disease (GD), Hashimoto's thyroiditis (HT), and primary thyroid failure]. Evolving knowledge of the human immune system and results of studies on thyroid autoimmunity have suggested to us for many years (1) that the cause of autoimmunity is instead multifactorial. We believe that some level of self-reactivity is a normal—indeed, necessary—aspect of immune function. The development of autoimmune disease involves genetic and environmental influences that amplify normal self-reactivity and which evolve over a lifetime. The course is not always unidirectional, since activation of autoregulatory responses can apparently reverse it. In this article we first provide an abbreviated summary of immune function and then review contemporary research on autoimmunity as related to the thyroid gland, including studies that begin to explain immune responses in molecular terms. Last, we offer a construction of AITD as a multifactorial process evolving through recognizable stages over years and attempt to integrate the experimental findings into this scheme.