The primary function of the epidermis is to provide a protective barrier against numerous environmental insults, including ultraviolet radiation (UVR). UVR, particularly in the UVB spectrum, is a potent carcinogen known to damage DNA directly or through the generation of free radicals. Although in the long term, protective measures such as apoptosis and inflammation may prove beneficial in safeguarding the epidermis against the propagation of potentially tumorigenic cells, after high-dose UV irradiation these biologic events may be acutely detrimental to the architectural and functional integrity of the tissue owing to rampant cell death and inflammatory responses, which can culminate in epidermal erosion and consequently loss of barrier functions. The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated by UVR and herein we identify p38 MAPK as a key modulator of these physiologic events. Mice treated with the p38 MAPK inhibitor SB202190 are protected against several detrimental effects of acute UV irradiation, namely, sunburn cell/apoptosis, inflammation, and a hyperproliferation response. Based on our results, selectively blocking p38 activation with the SB202190 inhibitor could prove beneficial in treating victims from severe sunburn or exposure to other chemical agents known to trigger the p38 pathway.