Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS) and several lymphoproliferative diseases. As with all herpesviruses, KSHV replicates in a biphasic manner, with the establishment of a latent, persistent infection from which reactivation occurs, resulting in the completion of the temporal lytic replication cycle and production of infectious virions. Herein, we discuss the impact of KSHV lytic replication on the host cell nucleus and nuclear-related pathways. We highlight the dramatic remodelling of the nuclear architecture driven by the formation of viral replication and transcription centres (vRTCs), and the implications for sub-nuclear organelles, and how pathways involved in DNA damage, ribosomal biogenesis and epitranscriptomic regulation are disrupted or modified during KSHV replication. These changes foster an environment favourable for KSHV replication and may provide novel targets and strategies for therapeutic intervention.