Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease with an estimated incidence of 1:6000 to 1:10 000 live birth caused by pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin) genes that together with TBC1D7 act as the main negative regulator of the mechanistic target of rapamycin (mTOR) signaling pathway. Mechanistic target of rapamycin further associates in 2 protein complexes, mTORC1 and mTORC2, that manifest distinct roles.1 In the brain, mTORC1 regulates protein and lipid synthesis, cell growth, metabolism, and autophagy and has established functions in neuronal excitability, memory formation, and learning. mTORC2 is primarily involved in the maintenance of cytoskeletal integrity and cell migration.1,2 Hyperactivation of the mTOR signaling pathway subsequent to loss-of-function variants in either TSC1 or TSC2 results in abnormal cellular morphology, proliferation, and multi-organ hamartomatosis.1 Sirolimus (rapamycin) and everolimus (Afinitor) are macrolide derivatives that were identified as potent mTORC1 inhibitors, and their clinical use demonstrated efficacy for the treatment of renal angiomyolipoma, subependymal giant cell astrocytoma (SEGA), and lymphangioleiomyomatosis.1 A mouse model of TSC with conditional inactivation of the Tsc1 gene in glial fibrillary acidic protein (GFAP)-positive cells (Tsc1GFAPCKO mice) manifested time-dependent control of epilepsy when treated with sirolimus. Early treatment prior to the development of clinical seizures at postnatal day 14 suppressed the onset of experimental epilepsy for the duration of treatment, while treatment after spontaneous seizures were well established and resulted in an improvement but not a full control of seizures.3 Clinical trials paralleled the preclinical experience, and treatment of patients with TSC-related medically refractory epilepsy with everolimus resulted in a significant reduction in seizure frequency, although most patients with TSC did not become seizure-free.4-6 Furthermore, epilepsy-related burden is only one of several challenging consequences of TSC, as patients typically also manifest autism spectrum disorder and a variable degree of intellectual disability.1,2 While modulating hyperactive mTOR pathway with everolimus may lead to a meaningful improvement in epilepsy, its effect on cognition and behavior remains less well defined. Although preclinical data suggested improvement, a 6-month long administration of everolimus to children with TSC in a randomized, placebo-controlled trial showed a possible trend but not a statistically significant improvement in neurocognitive functioning or in behavior, and similar results were noted in EXIST-3 substudy in Japan.5,7 Considering the logistical challenges of these trials (patient heterogeneity, confounding effects of medications, comorbid conditions, and others), results of these clinical studies hardly mean absolute lack of efficacy but rather highlight the biological complexity that underlies neurocognitive dysfunction in TSC. As illustrated in the Tsc1GFAPCKO model, sirolimus administration before the clinical onset of seizures ameliorated progressive astrogliosis and abnormal neuronal organization, and it suppressed the development of interictal and ictal abnormalities.3 Treatment timing may similarly be critical when aiming to salvage cognition. Furthermore, individual genetic background may influence the neurological phenotype and treatment response, and this variable is difficult to model in a mouse. The application of patient-specific induced pluripotent stem cells (iPSCs) is transcending some limits inherent to genetic mouse models since iPSCs preserve patients’ genetic background and are amenable to molecular research and drug testing.