Human rhinovirus (HRV)-induced wheezing illnesses in early life are a major risk factor for subsequent asthma development, and may contribute to induction and progression of airway remodeling (AR) seen in the airways of asthmatic subjects. Thickening of the lamina reticularis is a component of AR that is due to increased deposition of matrix proteins by mesenchymal cells that are increased in asthmatic airways, although the origin(s) of these cells are unclear. We have shown that two different strains of HRV, alone and in the presence of transforming growth factor-β1, caused phenotypic changes in epithelial cells consistent with the process of epithelial to mesenchymal transition. Viral replication was not essential for phenotypic changes, which appear to be mediated, in part, via activation of mitogen activated protein kinase pathways, and via induction of the transcription factor, SLUG. These data support a role for HRV in the development and progression of AR.