KSHV encodes several genes that are oncogenic, and/or promote cell growth and survival; however, their functions in KSHV-induced malignant transformation remain unclear. Using the genetic manipulation system, we have generated a library containing mutants of >95% KSHV genes. With these mutants, we are attempting to identify viral genes and their functional domains that are essential for KSHV cellular transformation of human primary endothelial cells. Once KSHV transformation genes are identified, we will further define signals transduced and cellular pathways targeted by these genes. These studies will define KSHV genes and their domains, and altered cellular pathways that are critical for KSHV malignant transformation, thus lead to a better understanding of KSHV-related pathogenesis.