The main barrier to the human skin resides in the stratum corneum(SC), which is approximately 10 – 30 microns thick and consists of layers of tightly packed dead skin cells. However, when the skin is extensively hydrated, changes occur in the SC which may induce a pathway for larger molecules to penetrate through this dense layer. Here, we report that extensive hydration of porcine skin for 6 – 10 hours creates gross changes in SC microstructure and results in a three-fold expansion in the stratum corneum thickness. By examining these changes through cryo-scanning electron microscopy, we present a model outlining the different stages of hydration of the SC. Due to the affinity of keratin for water, the corneocytes in the SC readily expand due to the influx of water during hydration. This causes individual corneocytes to swell and creates bending stresses at the edges of the corneocytes. With prolonged hydration, delamination of the lipid lamellae is observed as small dilations (holes) which may form large cisternae (water pools) are frequently observed in the cross-section of the SC. These results lead us to stress the importance of a sufficient hydration time in order to open up penetration pathways large enough for macromolecules to pass through the SC. By continually keeping the SC hydrated under an occlusive patch for extended periods, we are able to create these significant disruptions that may offer a safe and reversible method for macromolecular protein penetration through the skin.