Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway play a central role in multiple cellular functions such as cell proliferation and survival. The forkhead box O (FOXO) transcription factors are negatively regulated by the PI3K/AKT signaling pathway and considered to have inhibitory effect on cell proliferation. Psoriasis is a multifactorial disease with a strong genetic background and characterized by hyperproliferative keratinocyte. PI3K signaling regulates proliferation of keratinocyte by activating AKT and other targets, and by inducing FOXO downregulation. The amplification of PI3K and AKT and the loss of the FOXO are gradually being recognized in psoriatic lesions. The upstream and downstream of PI3K/AKT signaling molecules such as tumor suppressor phosphatase and tensin homolog (PTEN) and mammalian target of Rapamycin (mTOR), respectively, are also frequently altered in psoriasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and AKT in regulating hyperproliferation of keratinocyte, and the roles of the downstream targets FOXO in psoriasis. Finally, we summarized that PI3K/AKT/FOXO signaling and its upstream and downstream molecule which could be underlying therapeutic target for psoriasis. This article is part of a special issue entitled: PI3K-AKT-FOXO axis in psoriasis.