Akt2 is a pivotal player in a complex web of signaling pathways controlling cell growth, proliferation, and survival. The deregulation or aberrations of Akt2 have been associated with tumor progression, metastatic spread, and, lastly, chemoresistance. The impairment of its activity has gained more attention because Akt2 is intertwined with a range of signaling paths, including the Phosphatidylinositol 3 kinase/Akt/Mammalian target of rapamycin (PI3K/mTOR) signaling axis, which are involved in macromolecules synthesis and metabolism. Here, we focus on Akt2 because of its involvement in the acquisition of stem cell-like properties, responsible for invasiveness and chemoresistance, also promoted by Twist. We also suggest therapeutic strategies targeting Akt2 to overcome the drawbacks of current cancer therapies.