Abstract: Porcine circovirus virus type 2 (PCV2) is a major pathogen that causes postweaning multisystemic wasting syndrome (PMWS) and other swine-related diseases in piglets. Replicase (Rep) is a functional replication initiation protein encoded by the ORF1 gene participating in the DNA rolling loop replication of PCV2 by interacting with Rep′, another replication-related protein encoded by ORF. As an essential functional protein of PCV2, Rep could become a new target that can lead to breakthroughs in the research on antiviral therapy for PCV2, as most of the existing studies on the pathogenesis of PCV2 and vaccine have focused on Cap. This article reviewed the latest reports published in the world to systematically analyze Rep, especially, the critical roles and mechanisms that 8 known kinds of intracellular proteins interacted with it may play in the replication of PCV2. Furthermore, other cellular proteins that are possibly associated with the PCV2 Rep but not yet identified by the scientific communities are also included in the discussion for future exploration on the PCV2 pathogenesis.