<p>Surgical resection for drug-resistant focal epilepsy relies on the precise presurgical localization of the epileptogenic zone (EZ). Although [¹⁸F]FDG-PET has historically served as a diagnostic cornerstone, its clinical utility is often constrained by anatomy–metabolism decoupling. This non-specific glucose hypometabolism frequently extends beyond the true EZ due to the bystander effect, complicating surgical margin delineation in MRI-negative patients and those with focal cortical dysplasia (FCD). While [¹⁸F]FDG-PET and ictal SPECT remain the guideline-endorsed cornerstones of routine clinical care, this review explores the emerging investigational transition toward advanced multimodal molecular–structural fusion strategies. We evaluate novel PET radiotracers designed to target proximal pathophysiological mechanisms of epileptogenesis, including synaptic density degradation (SV2A), microglial-mediated neuroinflammation (TSPO), neurotransmitter system imbalances (GABA_A, mGluR5), and dysregulated amino acid metabolism (AMT). Furthermore, we outline the integration of these mechanism-based molecular probes with high-resolution isotropic 3D MRI frameworks and artificial intelligence-driven coregistration pipelines. Clinical evidence across various epilepsy subtypes demonstrates that this multimodal approach enhances the detection of subtle histopathological lesions, refines surgical boundaries, and optimizes invasive stereoelectroencephalography (SEEG) trajectories. Ultimately, transitioning to molecular–structural coupling provides a robust framework to advance precision epilepsy surgery and improve postoperative outcomes.</p> Graphical abstract <p></p>