Epstein-Barr virus (EBV) is a herpesvirus infecting >90% of the population. An EBV infection can be latent, where few genes are expressed, or lytic, where the entire viral gene complement is expressed to replicate the genome and produce infectious virions. EBV infects B cells, which are considered to be the latent reservoir of the virus, and epithelial cells, which are an important site of lytic replication. While lytic reactivation from latency in B cells has been extensively studied, the regulation of this process in epithelial cells is relatively uncharacterized. Furthermore, EBV infection of these two cell types is associated with malignancies such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. All EBV-associated cancers maintain a latent EBV infection and understanding how the EBV latent-to-lytic switch is regulated and maintained by cellular factors can give an understanding of not only how this event occurs, but also how cancers develop. In this thesis, I will show that three cellular proteins: p63, YAP, and TAZ, have differential effects on the ability of EBV to reactivate from latency.In Chapter 2 of my thesis, I will show that the p63 isoforms ΔNp63α and TAp63α inhibit EBV from undergoing lytic reactivation in epithelial cells and B cells, respectively. I will also demonstrate that ΔNp63α inhibits Z promoter activity. I found that ΔNp63α expression increases the expression of the lytic repressor c-myc, and decreases activity of the lytic enhancer p38 MAPK, indicating that ΔNp63α and TAp63α can inhibit EBV lytic reactivation through at least two mechanisms. In Chapter 3 of my thesis, I will demonstrate that the Hippo signaling effector genes YAP and TAZ induce lytic reactivation via the EBV immediate-early BZLF1 promoter and require the co-activator gene family TEADs for this effect. Finally, I show that YAP, TAZ, and TEADs are expressed in EBV-infected epithelial cell lines, but are not highly expressed in EBV-infected B cell lines. Thus, this phenomenon is an epithelial cell-specific mechanism by which the virus reactivates. My work indicates that cellular genes that are commonly upregulated in epithelial cancers regulate EBV lytic reactivation.