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In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate., Author Summary Kaposi's sarcoma-associated herpesvirus (KSHV) is an important human pathogen and, like all herpesviruses, establishes a state of permanent residency in the infected host called latency. Major sites of KSHV latency are cells of the immune system and cells lining blood vessels. In individuals with weakened immunity, inappropriate growth of these cells driven by the resident virus can give rise to primary effusion lymphoma and Kaposi's sarcoma, respectively. These life-threatening cancers are most common in patients with HIV/AIDS and have become a major source of mortality in parts of sub-Saharan Africa. Under appropriate stimuli, herpesviruses change their relationship with the host cell and begin to manufacture proteins required to assemble new infectious virus particles that can be released and spread. To achieve this, the virus hijacks key processes within the cell and conscripts them into producing viral proteins. In this study, we describe for the first time how KSHV carefully manipulates the host protein synthesis machinery during the switch from latency to this specialized infectious virus production mode. Our results show that although overall protein synthesis is diminished, key components of the host's protein manufacturing machinery are actually stimulated, presumably to accelerate viral protein production.