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Status epilepticus (SE) is a common neurological emergency in children, carrying significant risks of morbidity and mortality. Refractory SE (RSE) and super-refractory SE (SRSE) represent the most severe end of this spectrum and are among the most challenging clinical scenarios in pediatric neurology. This review addresses the key molecular and cellular mechanisms underlying the transition to refractoriness, including activity-dependent changes in GABAergic and glutamatergic neurotransmission and the activation of neuroinflammatory pathways, and discusses their implications for treatment. We further review current evidence on the pharmacological management of pediatric RSE and SRSE, from the rational use of sedating agents to less conventional strategies such as ketamine, the ketogenic diet, and immunomodulatory therapies. Understanding the pathophysiology of refractoriness is key to optimizing existing therapies and developing novel, mechanism-based approaches for children affected by this condition.