Tuberous sclerosis is a dominantly inherited genetic disorder, with a high frequency of new mutations, which has been shown through genetic linkage studies to be genetically heterogeneous. In this paper we summarize recent progress in linkage studies which indicate that there is one TSC gene on chromosome 9q34 which accounts for approximately 40% of cases and another on chromosome 16p13.3 which accounts for approximately 50% of cases. We discuss the map position of these TSC genes on chromosome 9q34 and 16p13.3. We discuss physical mapping data in these two regions. We postulate on the pathogenesis of TSC lesions and on the cause of the high frequency of new mutations. We present a strategy to progress from the mapping of the TSC genes to isolation of these genes.