The primary barrier to permeability in mammalian skin resides within the ∼15 μm thick outermost layer, the stratum corneum (SC) which is formed from anucleated corneocytes embedded in a lamellar lipid matrix. Studies of lipid structural organization in human SC have begun to provide a basis for understanding barrier function with the potential for elucidating how skin organization is altered in disease states. In contrast, the kinetics and mechanisms of the development of lamellar structures, lipid packing motifs, and domain formation have not been widely probed. Yet, molecular level information concerning the mechanisms and kinetics of lipid domain formation would help define potential pathways for permeation of hydrophobic species as well as to possibly provide clues as to why a variety of ceramides and additional chemical species are present in the SC. In addition, understanding the formation and dissipation kinetics of domains formed from particular ceramide and fatty acid species would aid in defining biological processes such as epidermal desquamation. The current study demonstrates the feasibility of utilizing IR spectroscopy for studying lateral phase separation and the development of the early stages of lamellar structure in skin lipid models formed from two fairly standard ternary equimolar mixtures, namely ceramide[NS]/stearic acid/cholesterol and ceramide[AS]/stearic acid/cholesterol mixtures. The IR measurements show that the following sequence of events occurs in ceramide[NS]/stearic acid/cholesterol mixtures: (1) rearrangements of H-bonds in the ceramide component, (2) formation of small ceramide domains and orthorhombic phases, followed by (3) rearrangement of H-bonds in stearic acid, and (4) formation of relatively large and pure orthorhombic domains of stearic acid, probably indicative of the onset of lamellar phase formation. Notably different kinetic behavior is observed for the stearic acid component in the ceramide[AS] mixture.