OBJECTIVES: To assess current understanding of humanistic and economic burden of tuberous sclerosis complex (TSC), a rare progressive genetic disorder characterized by benign tumors in multiple organ systems.  Common neurological manifestations include brain lesions, epilepsy, seizures, and mental retardation. METHODS: Using specified keywords related to TSC, we systematically searched MEDLINE- and EMBASE-indexed, English-language literature published between 5/2000 - 5/2010 , and non-indexed materials from governmental or professional organizations.  Included articles pertained to clinical, economic and humanistic burden of TSC in humans.  Excluded articles were molecular biology and genetic studies, and, to eliminate lower-value studies, case reports and studies enrolling <20 TSC patients. RESULTS: One hundred and nineteen articles were included, with 115 on clinical burden. While no therapies prevent disease progression, treatment of TSC and its neurological manifestations remains poorly defined by guidelines and focuses on symptom management. Caregiver burden is substantial, as many parents experience stress related to children’s basic needs, psychiatric diagnoses, low intelligence, behavioral problems, and seizures. While two survey studies explore caregiver burden, there are no studies on health-related quality of life in TSC patients. Also absent are cost of treatment and resource use associated with TSC, which are likely substantial for symptomatic subependymal giant cell astrocytomas (SEGAs) and medically refractory epilepsy that often require surgical resection to control symptoms and disease progression. There are no cost-effectiveness analyses or studies of indirect costs. Two analyses of the cost of genetic testing suggest that TSC is too rare to recommend population-wide screening. CONCLUSIONS: Few available data quantify the humanistic and economic burden of TSC. As a lifelong condition with disabling neurological manifestations and unmet clinical needs, the care and costs associated with TSC burden patients, caregivers, and society. Future research should determine total cost of disease, including probable high indirect costs of caregiver time and lost productivity.