Replication of the human genome relies on the presence of thousands of origins distributed along each of the
chromosomes. The activation of these origins occurs in a highly regulated manner to ensure that chromosomes are
faithfully duplicated only once during each cell cycle. Failure in this regulation can lead to abnormal cell proliferation, or/
and genomic instability, the hallmarks of cancer cells. The mechanisms determining how, when, and where origins are
activated remains still a mystery. However recent technological advances have facilitated the study of DNA replication
in a genome-wide scale, and have provided a wealth of information on several features of this process. Here we
present an overview of the current progress on our understanding of the initiation step of DNA replication in human
cells, and its relationship to abnormal cell proliferation.