Infantile spasms present a constellation of symptoms and laboratory findings that suggest a role of subcortical circuits in the pathogenesis of this illness. The clinical features of spasms and the influence of subcortical circuits in the regulation of the electroencephologram, along with frequent abnormalities in subcortical structure and functional anatomy, brain stem electrophysiology, sleep regulation, and subcortical neurotransmitter levels, point to the importance of subcortical circuits in the generation of spasms. Furthermore, laboratory evidence shows that modulation of subcortical nuclei may attenuate and ameliorate seizures. We review clinical evidence indicating abnormal function in subcortical circuits and present a hypothesis that the development of infantile spasms requires dysfunction in both cortical and subcortical circuits. The confluence of evidence suggesting a role of subcortical structures in the origin of spasms and laboratory data indicating an anticonvulsant role on some subcortical nuclei raise the possibility of novel approaches to the treatment of infantile spasms.