The Akt/PKB serine/threonine protein kinase consists of three isoforms: Akt-1, -2 and -3. Their overexpression has been detected in human cancers, but their roles in cancer progression are unclear. We investigated the impact of specific silencing of Akt1 and Akt2 on human lung cancer cell proliferation, colony growth, motility, and invasion in vitro as well as tumor growth in vivo using human Non-Small Cell Lung Cancer cells LNM35, and on the vascular tube formation using HUVEC cells. Although silencing of Akt1 decreased cellular invasion at least in part via COX-2 inhibition, it had almost no effect on cell motility, proliferation, colony formation, and angiogenesis. Transient as well as stable silencing of Akt2 resulted in a strong inhibition of Rb phosphorylation associated with a decrease in cellular proliferation and colony formation, leading to the inhibition of tumor growth in the xenograft model. Silencing of Akt2 also reduced cellular motility and invasion in vitro, presumably via COX-2 inhibition. Moreover, silencing of Akt2 in the HUVEC cells resulted in the inhibition of their spontaneous angiogenic phenotype. Altogether, these results indicate that Akt2 plays an important role in lung cancer progression and can be a promising target for lung cancer therapy.