A wide variety of tissue expansion techniques have been used for breast reconstruction, craniofacial surgery, and burn care in plastic reconstructive surgery. However, the basic mechanism by which skin and surrounding tissue respond to mechanical expansion remains unclear. Recent studies have revealed the biomechanical aspects of cells subjected to strain and various factors involved in the stretch-induced signal transduction pathway. In this regard, we have reported previously that mechanical force increases keratinocyte growth and protein synthesis and alters cell morphology. The mechanism by which strain causes an enhancement of cellular growth appears to be a network of several integrated cascades, implicating growth factors, cytoskeleton, and the protein kinase family. Recently, additional evidence has accumulated that mechanical strain stimulates signal transduction pathways that could trigger a series of cascades eventually leading to a new skin production. For example, we have evidence suggesting a key role for protein kinase C (PKC) in mechanosignaling as PKC is activated and translocated in keratinocytes subjected to strain in an isoform-specific manner. In this report, molecular mechanisms leading to enhancement of skin surface area are reviewed, and possible future applications are discussed.