Skin turbidity limits light based medical applications while increasing the risk of epidermal thermal injury. Collagen fibers are responsible for the majority of light scattering within skin. Chemicals, known as clearing agents, reduce tissue light scattering with the potential to increase the efficacy of light based imaging and therapeutic applications. Three hypotheses have been suggested for the clearing mechanism: index of refraction matching between clearing agent and collagen, tissue dehydration, and agent induced collagen structure perturbation. This study investigates optical clearing in skin while presenting a comprehensive clearing mechanism. Clearing was found to be a complex process with thermodynamic and kinetic components. Concentration gradients drive clearing agents to diffuse into skin and remove water. The introduction of clearing agents into the tissue reduces light scatter. The speed of clearing was found to increase with molecular size and number of hydroxyl groups. The molecular modeling program CHARMM suggests collagen affinity plays a major role in clearing agents’ ability to interact with collagen and remove bound water. Collagen solubility is a measure of clearing agent affinity for collagen and was found as a predictor of agent clearing potential. Increasing agent molecular size led to a greater reduction of fibrillogenesis with corresponding high collagen solubility. Raman spectroscopy quantified clearing agent induced dehydration of dermal collagen. Clearing agent ability to dehydrate dermal collagen corresponded with collagen affinity and the ability to clear tissue optically. The most effective clearing agents were found to remove bound water with the greatest efficacy. Replacement of collagen triple helix bound water by clearing agents with an index of refraction similar to collagen optically homogenizes skin tissue leading to a reduction in light scattering. Through dehydration of collagen with concomitant diffusion of clearing agent into collagen, the skin is homogenized leading to a large reduction in tissue light scattering.