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In selected cases, drug-resistant epilepsy can be safely managed with neuromodulation, leading to a significant reduction in disease burden. Summary: Experimental evidence has demonstrated that the primary neuromodulation modalities, vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), can modulate various brain circuits and reduce epileptic activity by decreasing neuronal hypersynchronization through multiple mechanisms at the molecular, cellular, and network levels. However, clear criteria for selecting among devices, determining optimal stimulation targets, and defining effective parameters to improve outcomes remain elusive. Key Messages: Neuromodulation represents a promising treatment strategy for drug-resistant epilepsy. Nevertheless, further research is essential to refine clinical decision-making. 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