Much has been learned about tuberous sclerosis complex (TSC) since it was described at the end of the nineteenth century. TSC was recognized to be a genetic disease with autosomal dominant inheritance in the early twentieth century. The prevalence in the general population is at least 1 in 10,000 with two-thirds of cases occurring sporadically and one-third of cases being familial. The disease exhibits variable expression which may cause mildly affected individuals to be undiagnosed. Because the aberrant or missing proteins which result in TSC have eluded investigators, a positional cloning approach has been pursued to find the mutated genes. Genetic linkages have been reported to chromosomes 9, 11, and 12. There is definite evidence for a TSC-causing locus on chromosome 9 which is thought to account for between one-third and one-half of all familial cases. Investigators have narrowed the location on chromosome 9 to approximately two megabases of physical distance. There is some evidence for a locus on chromosome 11 which probably accounts only for a small percentage of familial cases. The locus proposed on chromosome 12 was reported by a single group and has not been confirmed by other research groups. Evidence for genetic heterogeneity is abundant. There is definitely a TSC-causing locus on chromosome 9q (TSC-1) and there is at least one additional locus, maybe more than one. As the molecular basis of TSC unfolds, new insight will be gained about the protean nature of the disorder and the genetic heterogeneity.