Developmental and epileptic encephalopathies (DEEs) are severe neurological disorders characterized by childhood-onset seizures and significant developmental impairments. Seizures are often refractory to treatment with traditional antiseizure medications, which fail to address the underlying genetic and molecular mechanisms. This comprehensive review explores the evolving landscape of precision therapeutics for DEEs, focusing on mechanism-driven interventions across key pathophysiologic categories. Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies. For synaptic dysfunctions, innovative treatments such as chemical chaperones for STXBP1-related disorders and Ras-Raf-MEK-ERK inhibitors for SYNGAP1 pathologies are discussed. The review also examines precision interventions targeting cellular signaling pathways in tuberous sclerosis complex, epigenetic regulation in Rett syndrome, and metabolic interventions like ketogenic diets and targeted supplementation for specific genetic etiologies. Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized. Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care.