The commentary by Joseph R. Testa and Alfonso Bellacosa highlights the central role of AKT in tumorigenesis. AKT, a serine/threonine kinase, is a key player in various cellular processes that contribute to cancer development. Early studies identified AKT as an oncogene through the cloning of the v-akt gene from a transforming retrovirus. The AKT family, including AKT1, AKT2, and AKT3, is highly conserved and plays crucial roles in glucose homeostasis, cell cycle regulation, and apoptosis. Overexpression or amplification of these genes is frequently observed in human cancers, particularly in ovarian, pancreatic, gastric, and breast cancers. The activation of AKT involves a multistep process, including membrane translocation and phosphorylation by phosphatidylinositol 3-kinase (PI3K). Phosphorylation at specific residues, such as Thr-308/309 and Ser-473/474, is essential for AKT activation. Recent studies have revealed that AKT regulates the nuclear-cytoplasmic localization of key substrates involved in cell cycle and apoptosis, such as Mdm2 and p53. For example, AKT phosphorylates Mdm2, promoting its nuclear translocation and reducing p53 levels, which can lead to cell cycle arrest and apoptosis. Similarly, AKT can restrain the tumor suppressor p21WAF1 by preventing its nuclear localization, thereby enhancing cell cycle progression. The commentary also discusses the broader implications of AKT signaling in cancer, including its role in growth signal autonomy, tumor invasion, and metastasis. While overexpression of AKT isoforms can be oncogenic, wild-type forms of AKT are less likely to transform cells. However, the shared downstream targets of the AKT kinases suggest that they may have overlapping functions in oncogenic transformation. Overall, the expanding list of AKT substrates and its central role in multiple aspects of tumorigenesis highlight the potential for targeting the PI3K/AKT pathway as a therapeutic strategy in cancer treatment.The commentary by Joseph R. Testa and Alfonso Bellacosa highlights the central role of AKT in tumorigenesis. AKT, a serine/threonine kinase, is a key player in various cellular processes that contribute to cancer development. Early studies identified AKT as an oncogene through the cloning of the v-akt gene from a transforming retrovirus. The AKT family, including AKT1, AKT2, and AKT3, is highly conserved and plays crucial roles in glucose homeostasis, cell cycle regulation, and apoptosis. Overexpression or amplification of these genes is frequently observed in human cancers, particularly in ovarian, pancreatic, gastric, and breast cancers. The activation of AKT involves a multistep process, including membrane translocation and phosphorylation by phosphatidylinositol 3-kinase (PI3K). Phosphorylation at specific residues, such as Thr-308/309 and Ser-473/474, is essential for AKT activation. Recent studies have revealed that AKT regulates the nuclear-cytoplasmic localization of key substrates involved in cell cycle and apoptosis, such as Mdm2 and p53. For example, AKT phosphorylates Mdm2, promoting its nuclear translocation and reducing p53 levels, which can lead to cell cycle arrest and apoptosis. Similarly, AKT can restrain the tumor suppressor p21WAF1 by preventing its nuclear localization, thereby enhancing cell cycle progression. The commentary also discusses the broader implications of AKT signaling in cancer, including its role in growth signal autonomy, tumor invasion, and metastasis. While overexpression of AKT isoforms can be oncogenic, wild-type forms of AKT are less likely to transform cells. However, the shared downstream targets of the AKT kinases suggest that they may have overlapping functions in oncogenic transformation. Overall, the expanding list of AKT substrates and its central role in multiple aspects of tumorigenesis highlight the potential for targeting the PI3K/AKT pathway as a therapeutic strategy in cancer treatment.