Skin breakdown from mechanical stress application is a difficult health care problem for lower-limb amputees using prosthetic limbs. Post-operative treatments to encourage skin adaptation do exist, but are largely unsuccessful. Potentially, by understanding skin adaptation on a molecular level, appropriate biomolecules can be identified and then delivered to skin to encourage adaptation in at-risk patients. Based from a critical review of the literature, it is expected that adaptation occurs by forming new collagen fibrils with larger diameters as opposed to increasing diameters of existing fibrils. Small collagen fibril breakdown by stress activated metalloproteinases is expected to be followed by increased expressions of decorin, biglycan, fibromodulin, lumican, thrombospondin-2, and collagens I and III, facilitating formation of new fibrils with larger diameters. After remodeling, total collagen fibril cross-sectional area is expected to return to baseline values since increased collagen content would increase mass and be redundant towards the purpose of adaptation.