The major catastrophic epileptic syndromes of childhood include infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonus epilepsies (PMEs). Although each of these syndromes manifests in an age-specific manner and is defined by distinct electroclinical features, they are all refractory to medical therapy and are invariably associated with psychomotor deficits, and in the most severe cases, either epileptic encephalopathy or progressive neurodegeneration. While much has been written about the clinical features and natural history of the catastrophic epilepsies, very little is known about the underlying pathophysiology. Progress in our understanding and treatment of these conditions has been hampered by the lack of suitable animal models in which putative mechanisms and novel targets for intervention could be rigorously studied. Nevertheless, recent clinical and basic investigations have identified certain mechanisms that may be relevant to their pathogenesis. In this review, three major hypotheses regarding the pathophysiology of infantile spasms are highlighted: the corticotropin-releasing hormone (CRH) hypothesis, the N-methyl-D-aspartate (NMDA) hypothesis, and the serotonin-kynurenine hypothesis. One or more of these mechanisms may be relevant in part to later-onset catastrophic epilepsies since infantile spasms can persist into later childhood and, like Lennox-Gastaut syndrome, well into adulthood. There is a profound need to develop more relevant animal models of the developmental encephalopathic epilepsies to truly develop better therapeutic strategies for these catastrophic disorders.