It is the purpose of this review to demonstrate that oral isotretinoin treatment restores all major pathogenetic factors of acne vulgaris by upregulation of the nuclear transcription factor FoxO1, which will be shown to be the major target of retinoid action. Nuclear FoxO1 deficiency is the result of increased growth factor signaling with activated phosphoinositol-3-kinase (PI3K) and Akt kinase during growth hormone signaling of puberty and increased insulin/IGF-1 signaling due to consumption of insulinotropic milk/dairy products as well as hyperglycemic carbohydrates of Western diet. Nuclear FoxO1 deficiency increases androgen receptor transactivation and modifies the activity of important nuclear receptors and key genes involved in pilosebaceous keratinocyte proliferation, sebaceous lipogenesis and expression of perifollicular inflammatory cytokines. Isotretinoin-induced upregulation of nuclear FoxO1 is proposed to be responsible for the mode of action of isotretinoin on all major pathogenetic factors in acne. Acne pathogenesis can be explained at the genomic level of transcriptional regulation. All major events in acne pathogenesis as well as all major effects of isotretinoin treatment appear to be related to modifications of the PI3K/Akt/FoxO1 signaling pathway, the well-known oncogenic pathway. These insights extend our understanding of FoxO1-mediated retinoid action in acne and other hyperproliferative skin diseases, cancer chemoprevention and cutaneous immune regulation. Understanding FoxO´s pivotal regulatory role in acne allows the development of novel treatment strategies and dietary interventions in acne which focus on the restoration of growth factor- and diet-induced imbalances of nuclear FoxO protein levels.