Scleral fibroblasts are involved in scleral remodeling during axial elongation in myopia. Mechanical load is a potent stimulator of gene expression. This study seeks to identify changes in gene expression of scleral fibroblasts in response to mechanical load and speculate on possible mechanisms of scleral remodeling in the development of myopia. Human scleral fibroblasts (HSFs) were mechanically stretched for 30 min and 24 hr. A gene microarray analysis was used to measure changes in gene expression. A total of 237 genes revealed differential and significant changes in expression (P<0.01) after 30 min of stretching. Of these, 28 unexpressed genes began to be expressed (turned on), while 31 expressed genes were no longer expressed (turned off). After 24 hr, 308 genes showed reproducible changes in expression (P<0.01), while 29 genes were turned on and 17 genes were turned off. After 30 min, 25 genes showed at least a threefold change in expression. These included genes for cell receptors, protein kinases, cell growth/differentiation factors, extracellular matrix (ECM) proteins, lipid metabolism, protein metabolism, transcription factors, binding proteins and water channels. After 24 hr, 21 genes showed at least a threefold change in expression. These included genes for cell receptors, protein kinases, cell growth/differentiation factors, lipid metabolism, ECM proteins, transcription factors, and carbohydrate metabolism. RT-PCR and Southern blotting confirmed the changes in expression of selected genes. In this study we identified a large number of early and late mechanical response genes in HSFs. These changes in gene expression will provide potential candidate genes that might be involved in scleral remodeling during axial elongation in myopia.