The life cycle of KSHV, latency versus lytic replication, is mainly determined at the transcriptional regulation level. A viral immediate-early gene product, replication and transcription activator (RTA), has been identified as the molecular switch for initiation of the lytic gene expression program from latency. Here we review progress on two key questions: how RTA gene expression is controlled by viral proteins and cellular signals and how RTA regulates the expression of downstream viral genes. We summarize the interactions of RTA with cellular and other viral proteins. We also discuss critical issues that must be addressed in the near future.