This chapter focuses on the neuroimaging alterations in fatal familial insomnia (FFI) and their pathological correlates. Autonomic studies in FFI have shown higher blood pressure and heart rate in the resting state with elevated levels of norepinephrine, which further increase on postural challenge or Valsalva maneuver. The two- to three fold increases in serum norepinephrine level and the absence of the physiological nocturnal peak of melatonin secretion are the prominent hormonal markers of the disease. The neuropathological hallmark of FFI is severe atrophy of the anterior ventral and mediodorsal thalamic nuclei with loss of 80-90% of the neurons and two- to three fold increase in astroglial cells, whereas spongiosis is conspicuously absent. FFI is probably the most challenging of transmissible spongiform encephalopathies (TSEs) to diagnose because brain lesions are confined to the thalamus. Brain conventional magnetic resonance imaging (MRI) shows no specific changes in familial or sporadic forms of FI.