Cells require the ability to appropriately respond to signals in their extracellular environment. To initiate, inhibit and control these processes, the cell has developed a complex network of signaling cascades. The phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways regulate several responses including mitosis, apoptosis, motility, proliferation, differentiation and many others. It is not surprising, therefore, that many viruses target the PI3K and MAPK pathways as a means to manipulate cellular function. Recently, Kaposi's sarcoma-associated herpes virus (KSHV) has been added to the list. KSHV manipulates the PI3K and MAPK pathways to control such divergent processes as cell survival, cellular migration, immune responses, and to control its own reactivation and lytic replication. Manipulation of the PI3K and MAPK pathways also plays a role in malignant transformation. Here, the authors review the potential to target the PI3K and MAPK signaling pathways to inhibit KSHV infection and pathogenesis.