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Among these approaches, mass spectrometry imaging (MSI) provides a label-free, in situ visualization of diverse molecular classes, including metabolites, lipids, proteins, and glycans. Recent advances in instrumentation, sample preparation, and data acquisition have pushed MSI into the field of single-cell analysis, providing unprecedented access to cellular heterogeneity and molecular states across biological contexts. Here, we review current single-cell MSI platforms and highlight key innovations that have improved spatial resolution, sensitivity, and throughput. Presented examples from published workflows highlight the variability in strategies for cell isolation, capture, and data acquisition. The three main ionization techniques of desorption electrospray ionization (DESI), secondary ion mass spectrometry (SIMS), and matrix-assisted laser desorption ionization (MALDI) are highlighted for their capabilities to generate robust single-cell multi-omics profiling. We outline future directions for the field and the potential of single-cell MSI to impact translational spatial omic research and precision medicine.<\/jats:p>","DOI":"10.1007\/s00216-026-06644-6","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:30:06Z","timestamp":1782988206000},"page":"6591-6603","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-cell mass spectrometry imaging: platform advances for multimodal spatial omics"],"prefix":"10.1007","volume":"418","author":[{"given":"Lauren E.","family":"Hill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsay E. 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