Phosphorylation of Akt at Ser473 is a key event in the activation of the protein kinase B (PKB), commonly known as Akt. This modification is essential for the full activation of Akt and its downstream signaling pathways, which play a crucial role in regulating cell survival, growth, and metabolism. The phosphorylation at Ser473 is often used as a biomarker for the activation status of Akt. In the context of cancer, the activation of the PI3K/Akt pathway is frequently dysregulated, and Akt activity has been implicated in tumorigenesis, making it a potential therapeutic target. The level of phosphorylated Akt (Ser473) has been correlated with clinical outcomes in various cancers, although the specific associations can vary between different tumor types and studies. Moreover, the phosphorylation of Akt at Ser473 is regulated by various cellular stresses, including endoplasmic reticulum (ER) stress. ER stress can modulate Akt substrate specificity and activity in a severity-dependent manner, which has implications for the development of therapeutic strategies targeting the Akt pathway.