While the formation of tumors in TSC has long been attributed to the contribution of a “second-hit” loss of the normal TSC1/2 allele, recent research has shown that many tumors, especially cortical tubers, lack a second-hit, raising the possibility of an alternate pathway for tumorigenesis that depends on monoallelic inactivation of TSC1/212. The gene discussed is TSC1; the disease is tuberous sclerosis.