Fatal Familial Insomnia (FFI) is an autosomal dominant prion disease, characterized by prominent degeneration of the thalamus and involving impaired control of the sleep-wake cycle and of autonomic and endocrine functions. Profound alterations in the sleep-wake cycle consist of progressive decrease or complete absence of sleep activity and loss of any intrinsic cyclic organization of residual sleep. Unbalanced sympathergic activation with preserved parasympathetic drive, associated with chronic secondary hypertension and loss of the physiological nocturnal decrease in blood pressure constitute the characteristic autonomic changes. Neuroendocrine studies document hypercortisolism with abnormal feed-back suppression of adrenocorticotrophic hormone, constantly elevated catecholamine levels and abnormal secretory patterns of growth hormone, prolactin and melatonin. Advanced stages of the disease are invariably characterized by the disappearance of any circadian autonomic and neuroendocrine rhythmicity. FFI represents a model disease emphasizing the correlations among the different sleep, autonomic and neuroendocrine functions. Clinico-pathological correlations demonstrate the role of the thalamus as an integrative neural structure placed between the limbic system and the hypothalamus and controlling the homeostatic balance of the organism.