Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. To persist and replicate within host cells, KSHV encodes proteins that modulate different signaling pathways. Manipulation of cell survival and proliferative networks by KSHV can promote the development of KSHV-associated malignancies. In this review, we discuss recent updates on KSHV pathogenesis and the viral life cycle. We focus on proteins encoded by KSHV that modulate the phosphatidylinositol-4,5-bisphosphate 3 kinase and extracellular signal-regulated kinases 1/2 pathways to create an environment favorable for viral replication and the development of KSHV malignancies.