Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy defined by the clinical triad of multiple seizure types, including tonic seizures and atypical absence seizures; specific pathological electroencephalogram (EEG) patterns, (slow spike-and-wave (SSW) and generalized paroxysmal fast activity (GPFA); and developmental delay or intellectual disability.1 LGS arises from diverse genetic, structural and metabolic causes, but typically evolves from earlier epilepsy, over approximately two years, by some estimates.2 It is thought that various inciting factors can destabilize shared neuronal circuits, leading to pathological "secondary network" evolution to LGS. In humans, the secondary network has been characterized in seminal studies using EEG-fMRI, demonstrating that SSW and GPFA are associated with abnormal patterns of activity across large networks, including the attention, default mode, and cortical-thalamic networks.3, 4, 5 These patterns are consistent across LGS cases with different etiologies.3, 4, 5 While recent studies highlight the promise of resective surgery and corpus callosotomy for LGS where appropriate,6 the vast majority of people with LGS have drug-resistant epilepsy, together with comorbidities such as intellectual disability, autism, sleep disorders and other neurological impairments. The lack of effective treatments relates to persistent gaps in knowledge regarding underlying biological mechanisms.7 Preclinical models can be used to address these gaps and enable new strategies for mechanism-based, disease-modifying therapeutics. In this focused review, we provide an overview of preclinical models of LGS and examples of insights gained. We conclude with a discussion of priorities for future preclinical research to promote improved, comprehensive care for people with LGS.