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Understanding the mechanisms governing the penetration of substances into the skin is crucial for the development of safe and effective topical drug delivery systems and skincare products. This study examined the partitioning of model permeants into human skin, by assessing six substances with diverse logP values. We employed stimulated Raman scattering (SRS) microscopy, an ambient, label-free optical imaging technique known for its ability to provide chemical distribution with subcellular resolution. Our investigation assessed partitioning into the two primary pathways through which substances traverse the skin: the intercellular lipid matrix and the intracellular route via corneocyte cells. We observed that the partitioning behaviour was strongly influenced by the lipophilicity of the molecule, with lipophilic compounds showing greater affinity for intercellular matrix with increased lipophilicity. Conversely, hydrophilic molecules demonstrated a preference for corneocyte cells, with their affinity increasing with increased hydrophilicity. The findings contribute to our understanding of the mechanisms underlying topical delivery and offer important implications and new methods beneficial for the development of safe and effective topical products. In addition, the methods presented could be valuable to reveal changes in drug partitioning or to assess targeting approaches in diseased skin models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)