The stratum corneum (SC), the outermost layer of the skin, provides the body with a physiologically essential barrier to unregulated water loss and the influx of exogenous substances. Furthermore, the 10–20 micron thick SC, composed of overlapping protein-rich corneocytes surrounded by a heterogeneous multilamellar lipid matrix, displays tremendous mechanical cohesion and thermal integrity. To understand the contribution of these components to SC mechanical properties requires building a complete mechanical model of the skin. In this study we focus on modelling the hierarchical microstructure of the lipid phase and its relation to mechanical properties using a combination of atomistic and mesoscale simulations. The modelling approaches are parameterised with experimental data from FT-IR spectroscopy, X-ray scattering and, in the case of the mesoscale simulations, with detailed density profiles derived from atomic models. The atomistic models are used to probe the role of specific lipid species in maintaining the thermal and structural stability of the SC extracellular lipid matrix and to investigate the role of hydrogen bonding networks in SC lipid cohesion. Mesoscale models are used to investigate domain formation and lipid bilayer organisation on length and time scales inaccessible with atomistic models. These coarse grained models display transitions between ordered hexagonal gel phases and fluid phases, reproducing the experimentally observed ordering of the hydrophilic and hydrophobic regions.