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Detailed knowledge about the role of the <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> proteins in regulating the activity of the mammalian target of rapamycin complex 1 (<jats:styled-content style=\"fixed-case\">mTORC1<\/jats:styled-content>) underlies this paradigm\u2010shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>, including pivotal discoveries using next\u2010generation sequencing (<jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content>). For example, the pathogenesis of angiofibromas is now known to involve <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content>\u2010induced mutations, and the pathogenesis of multifocal renal cell carcinoma (<jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content>) in <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> is now known to result from distinct second\u2010hit mutations. In parallel, the pathological features of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated tumours, including <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated renal cell carcinoma, continue to be defined, despite the fact that <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> was first described 180 years ago. Here, we review recent discoveries related to the pathological features and genetic pathogenesis of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\u2010associated tumours. Copyright \u00a9 2016 Pathological Society of Great Britain and Ireland. 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