There is an extensive list of primary published work related to the nuclear matrix (NM). Here we review the aspects that are required to understand its relationship with DNA replication, while highlighting some of the difficulties in studying such a structure, and possible differences that arise from the choice of model system. We consider NM attachment regions of DNA and discuss their characteristics and potential function before reviewing data that deal specifically with functional interaction with DNA replication factors. Data have long existed indicating that newly synthesized DNA is associated with a nuclease-resistant NM, allowing the conclusion that the elongation step of DNA synthesis is immobilized within the nucleus. We review in more detail the emerging data that suggest that prereplication complex proteins and origins of replication are transiently recruited to the NM during late G1 and early S-phase. Collectively, these data suggest that the initiation step of the DNA replication process is also immobilized by attachment to the NM. We outline models that discuss the possible spatial relationships and highlight the emerging evidence that suggests there may be important differences between cell types.