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Historically, these outcomes have been interpreted through the lens of classical drug resistance driven by heritable genetic mutations. However, drug responses are increasingly recognised to extend beyond resistance and include distinct but related phenomena such as hypersensitivity, tolerance, and persistence. Dissecting this range of responses in\n                    <jats:italic>Leishmania<\/jats:italic>\n                    requires approaches that capture both heritable genetic variation and dynamic cellular states. Here, we highlight how emerging genomics and perturb-omics technologies can resolve mechanisms underlying diverse drug responses. We emphasise that their impact depends on state-aware experimental design, including calibrated drug-selection, varied exposure regimens, and strategies to isolate rare persister populations. Together, these approaches provide a framework to move beyond resistance-centric models towards a more comprehensive understanding of parasite drug response.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014331","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:25:32Z","timestamp":1782321932000},"page":"e1014331","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Beyond resistance: Emerging methods to dissect drug responses in Leishmania"],"prefix":"10.1371","volume":"22","author":[{"given":"Beatriz Cristina Dias","family":"de Oliveira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Arias del Angel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Herrmann May","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata Anna","family":"Domagalska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-2649","authenticated-orcid":true,"given":"Tom","family":"Beneke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ppat.1014331.ref001","doi-asserted-by":"crossref","DOI":"10.3389\/fitd.2022.837460","article-title":"Tackling drug resistance and other causes of treatment failure in Leishmaniasis","volume":"3","author":"GJ Wijnant","year":"2022","journal-title":"Front Trop Dis"},{"issue":"4","key":"ppat.1014331.ref002","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.pt.2023.01.012","article-title":"Drug resistance in Leishmania: does it really matter?","volume":"39","author":"MA Domagalska","year":"2023","journal-title":"Trends Parasitol"},{"key":"ppat.1014331.ref003","article-title":"Molecular mechanisms of persistence in protozoan parasites","volume":"11","author":"A Tarannum 3","year":"2023","journal-title":"Microorganisms"},{"key":"ppat.1014331.ref004","doi-asserted-by":"crossref","first-page":"102069","DOI":"10.1016\/j.tranon.2024.102069","article-title":"Drug tolerance and persistence in bacteria, fungi and cancer cells: role of non-genetic heterogeneity","volume":"49","author":"I El Meouche","year":"2024","journal-title":"Transl Oncol"},{"issue":"2","key":"ppat.1014331.ref005","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.pt.2013.12.004","article-title":"Post kala-azar dermal leishmaniasis: an unresolved mystery","volume":"30","author":"D Mukhopadhyay","year":"2014","journal-title":"Trends Parasitol"},{"issue":"10","key":"ppat.1014331.ref006","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41579-019-0238-x","article-title":"Protozoan persister-like cells and drug treatment failure","volume":"17","author":"MP Barrett","year":"2019","journal-title":"Nat Rev Microbiol"},{"issue":"1","key":"ppat.1014331.ref007","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41579-022-00777-y","article-title":"Anti-trypanosomatid drug discovery: progress and challenges","volume":"21","author":"M De Rycker","year":"2023","journal-title":"Nat Rev Microbiol"},{"issue":"12","key":"ppat.1014331.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0007900","article-title":"Genomes of Leishmania parasites directly sequenced from patients with visceral leishmaniasis in the Indian subcontinent","volume":"13","author":"MA Domagalska","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"key":"ppat.1014331.ref009","doi-asserted-by":"crossref","unstructured":"Negreira GH, Monsieurs P, Dujardin JC, Domagalska MA. 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