Human tumor viruses contribute to 15-20% of human cancers worldwide. Kaposi’s sarcoma herpesvirus (KSHV) is an etiological agent for Kaposi’s sarcoma (KS) and two other malignancies. KS is the most common cancer in HIV-infected untreated individuals and remains a primary cause of cancer deaths in many subequatorial African countries as a result of the AIDS pandemic. This book first introduces an unbiased gain-of-function human kinome cDNA screen on KSHV reactivation in infected human cells. By developing a novel 3D cell culture model reflecting the context of virus-host cell interaction, this book further reveals the first lymphatic-specific endothelial-to-mesenchymal transition (EndMT) induced by a human tumor virus, giving rise to infected, invasive cells, and providing the virus a permissive cellular microenvironment for efficient spread of the virus. This book should shed lights on understanding the long-term persistence of oncogenic infectious agents in infected individuals, allowing time for the multi-step tumorigenesis. It should also be especially useful for professionals who are interested in developing targeted therapies to prevent or at least slow down KS progression.