The PI3K-AKT network, which is activated by cytokines or growth factors, mediates intracellular signals to regulate a variety of cellular responses, including antiapoptosis, proliferation, cell cycling, protein synthesis, glucose metabolism, and telomere activity. Genomic mutations, alterations of the PI3K-AKT regulatory network, underlie such diseases as cancer, glucose intolerance (diabetes mellitus), schizophrenia, and/or autoimmune diseases. In addition to direct tumorigenesis involvement by genetically altering human cancer, the PI3K-AKT network underlies the clinical manifestation of different stages of tumorigenic viral infection, such as latent and chronic infection, and malignant transformation of Epstein-Barr, hepatitis C, hepatitis B, and human immunodeficiency virus (HIV) viruses. We summarize updated knowledge on the PI3K-AKT network underlying different phathological viral and/or bacterial infections. Antiviral activity engendered by suppressing of PI3K-AKT activity, rather than directly targeting anticancer activity via oncogenes, may thus open up ways to prevent malignant transformation by tumorigenic viral infection.