Certain syndromes of extreme insulin resistance are the result of negative-dominant mutations of the insulin receptor. The insulin-receptor heterotetramer appears to be the minimal functional unit for insulin signal transduction probably due to a requirement for intersubunit interactions. The observation that insulin and insulinlike growth factor I receptors can be found in hybrid heterotetramers suggests that insulin receptors can be composed of heterodimers that are the products of separate genes. Such a structure provides a potential molecular mechanism for negative-dominant receptor mutations.