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With the widely increasing implementation of modern next generation sequencing (NGS) technologies in routine molecular pathology practice, the fraction of cancers with a definite or probable hereditary background has been steadily increasing. Currently, it is assumed that 5-10% of all malignancies develop in the context of germline predisposition diseases. Not rarely, the diagnosis and recognition of cancer predisposition syndromes rely on distinctive histopathological and/or immunophenotypical findings that proved to be highly reliable and reproducible in uncovering hereditary neoplastic diseases that would otherwise have gone undetected by clinicians. This is especially true in patients with new mutations and, hence, negative family history. Examples of such neoplasms are the fumarate hydratase-deficient renal cell carcinoma (FH-RCC), succinate dehydrogenase-deficient RCC (SDH-RCC), and hereditary gastrointestinal stromal tumor (GIST) syndromes. Notably, many of these inherited cancer syndromes may present as unifocal lesions at advanced age of onset so that they are mostly misinterpreted as sporadic on clinical grounds. The availability of effective disease-specific specialized cancer screening and follow-up programs for several hereditary cancer syndromes underlines the importance of timely recognition of these disorders to enable enrollment of "at-risk individuals" in such programs for early detection and timely prevention/treatment of these mostly aggressive neoplasms. This review highlights and discusses the major clinicopathological, topographic-anatomical, and histological features that are highly suggestive of a hereditary neoplastic disease. The details of some of the entities are dealt with in review articles devoted to them in this special issue.