Squamous cell carcinoma (SCC) occurs 65 to 250 times more frequently in solid organ transplant patients than in the general population. These patients must receive life-long immunosuppressive treatment with calcineurin inhibitors, mainly cyclosporin A or tacrolimus, to avoid organ rejection. Thus, immunosuppression has been widely assumed to be the cause of the higher SCC incidence in these patients. However, recent evidence suggests that calcineurin inhibitors might act directly to induce keratinocyte tumorigenic transformation in an ultraviolet (UV) light-dependent manner by impairing nucleotide excision repair gene expression. Although tacrolimus is more widely used than cyclosporin A, most studies have focused on the latter, with no published data showing the in vivo effects of tacrolimus on skin tumorigenesis. Here, by using an in vitro model, we aim to investigate the potential of Q-2361, a tacrolimus antagonist, to reverse the carcinogenic effect of tacrolimus in UVB-irradiated human keratinocytes. We will characterize the impact of both tacrolimus and Q-2361 in keratinocyte and SCC cell survival, proliferation, DNA damage and pro-inflammatory cytokine expression upon UVB treatment. Moreover, we will investigate the influence of tacrolimus and Q-2361 on DNA repair gene and cytokine expression in vivo in mouse ear skin after exposure to UVB. Finally, we will further investigate the protective effects of local Q-2361 treatment against skin carcinogenesis in tacrolimus-treated, immunocompromised mice.