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Their clinical manifestations are diverse, ranging from indolent lesions to aggressive systemic disease. Over recent decades, advances in genomic profiling have transformed the biological understanding of these conditions. The discovery of recurrent oncogenic mutations has reframed histiocytoses from primary inflammatory disorders to myeloid neoplasms, with a notable dependence on aberrant mitogen\u2010activated protein kinase (MAPK) signalling. Novel genetic drivers continue to be uncovered, with many alterations correlating with distinct clinical and pathological phenotypes. Parallel studies have refined the understanding of disease ontogeny, demonstrating that diverse histiocytoses originate from haematopoietic stem\/progenitor cells. In Langerhans cell histiocytosis, the differentiation stage of the mutated precursor cell is considered an important \u2014 but not the sole \u2014 determinant of disease extent and severity. Additional evidence suggests that specific clinical manifestations, such as neurodegenerative disease, may result from somatic mosaicism affecting tissue\u2010resident macrophages derived from yolk sac progenitors. Collectively, these findings refine histiocytosis diagnosis, risk stratification, disease monitoring and treatment, with robust activity of kinase inhibitors in patients with severe or refractory disease. In this review, we synthesise recent genomic insights into histiocytosis development and variation, while addressing remaining questions and future directions. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70081","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T13:08:56Z","timestamp":1779887336000},"page":"23-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Histiocytosis development and clinical variation through the lens of genomics"],"prefix":"10.1002","volume":"270","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9793-7032","authenticated-orcid":false,"given":"Paul G","family":"Kemps","sequence":"first","affiliation":[{"name":"Department 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