ABSTRACT Graft-versus-host disease (GVHD) is a common complication and the leading cause of non-relapse mortality among patients after receiving allogenic hematopoietic stem cell transplantation. The skin is the most commonly affected organ in both the acute and chronic forms of this disease. Treatment options are limited, and the current standard therapy is high dose systemic corticosteroids, which is in itself associated with significant morbidity and mortality. There is therefore a great need for novel treatment options for cutaneous GVHD. While the exact cause of GVHD is unclear, it involves a complex interaction between the donor immune cells and the recipient cells. Studies to date are primarily focused on immune cells. Little is understood about the role of recipient cells such as keratinocytes that form the principal barrier of the skin and oral mucosa. Our preliminary studies show that MEK is highly activated in keratinocytes of GVHD skin and oral lesions and that keratinocyte-targeted MEK activation in mice results in the development of a range of skin and oral lesions resembling those of human GVHD. These findings lead us to hypothesize that MEK activation in skin cells plays a major role in the development of cutaneous GVHD and that topical MEK-inhibition can be topically targeted for therapy. To test these hypotheses, we propose two specific aims: 1) to determine the effects of topical MEK-inhibition on preclinical models of GVHD; 2) to establish the utility of pMEK and its downstream targets as skin-based biomarkers for GVHD. We anticipate that completion of this study will lead to the development of skin-based biomarkers and novel topical treatment strategies that may benefit many transplant patients.