The transcription factor Nrf2 is a key regulator of the cellular stress response through the regulation of antioxidant enzymes and cytoprotective proteins. Therefore, pharmacological activation of Nrf2 is considered as a promising strategy for skin protection and cancer prevention. However, little is as yet known about the function of Nrf2 in the skin and the consequences of Nrf2 activation. We previously showed that loss of Nrf2 causes delayed wound healing and strongly enhances skin carcinogenesis. However, we also found that strong and prolonged Nrf2 activation causes major abnormalities in the epidermis and the pilosebaceous unit through regulation of genes involved in epidermal barrier function and sebocyte proliferation. Mild activation of Nrf2 in keratinocytes did not result in obvious skin abnormalities under unchallenged conditions, but it strongly accelerated skin carcinogenesis through activation of novel Nrf2 target genes involved in metabolism, cell survival and cell adhesion. These negative consequences of Nrf2 activation need to be considered when Nrf2 activators are used for skin protection or cancer prevention in patients.