Fibroblasts play a major role in tissue repair and remodeling. Their differentiation into myofibroblasts, marked by increased expression of smooth muscle specific -actin (-SMA), is believed to be important in wound healing and fibrosis. We have recently described a role for MK2 in this phenotypic differentiation in culture. In this report we demonstrate that MK2 also regulates myofibroblasts in vivo. Disruption of MK2 in mice prevented myofibroblast formation in a model of pulmonary fibrosis. However, MK2 disruption and consequent lack of myofibroblast formation exacerbated fibrosis rather than ameliorate it as previously postulated. When mice lacking MK2 (MK2^-/-) were exposed to bleomycin, more collagen accumulated and more fibroblasts populated fibrotic regions in their lungs than in similarly treated wild type mice. While there were many vimentin-positive fibroblasts in the bleomycin-treated MK2^-/- mouse lungs, few -SMA-positive cells were observed in these lungs compared to wild type lungs. siRNA against MK2 reduced -SMA expression in wild type mouse embryonic fibroblasts (MEF), while expressing constitutively active MK2 in MK2^-/- MEF significantly increased -SMA expression. MK2^-/- MEF proliferated at a faster rate and produced more collagen, however they migrated at a slower rate than wild type MEF. Overexpressing phosphomimicking HSP27, an MK2 target, did not reverse the effect of MK2 disruption on fibroblast migration. MK2 disruption did not affect Smad2 activation by TGF. Thus MK2 appears to mediate myofibroblast differentiation, and inhibiting that differentiation might contribute to fibrosis rather than protect against it.