The highly orchestrated process of DNA replication ensures the accurate inheritance of genetic information from one cell generation to the next. The exact execution of DNA replication depends on a large number of proteins that are being studied extensively in the cell cycle field. Some of these proteins, such as the minichromosome maintenance proteins (MCMs), are essential for the process of DNA replication itself. Others such as geminin are specifically required to limit DNA replication to once per cell cycle. Together, these proteins protect the stability of the human genome in cycling cells. Their expression has been compared with routinely used proliferation markers, such as Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA), which fulfil the requirements of molecular tumour markers to varying extents. However, it is with regard to the depth of our understanding of antigen biology that the MCM proteins and geminin qualify exceptionally well as novel cell-cycle biomarkers for routine use in clinical practice, particularly in cancer detection and estimation of prognosis. Expression microarray analysis has also independently identified MCMs and their interacting proteins as determinants of the inherent aggressiveness of a wide range of epithelial malignancies.