Our goal is to understand how mammalian chromosomes are organized within the nucleus to carry out their functions. DNA replication provides an excellent forum in which to study chromosome structure and function. Structural and functional units of chromosomes replicate coordinately, often through the synchronous firing of clusters of replication origins that encompass domains of approximately 0.5 Mb. Each of these replication domains is programmed to replicate at a specific time during S-phase. In general, transcriptionally active (euchromatin) domains replicate early in S-phase, and transcriptionally silent (heterochromatin) domains replicate late. Programmed changes in replication timing accompany key stages of animal development and are often coupled to changes in gene expression. Our working hypothesis is that structural, functional, and replication domains share topographical boundaries and represent basic units of chromosome organization. We would like to understand what regulates where and when replication begins, how developmental cues communicate with the cell-cycle machinery to elicit changes in the program for replication and how that program is disrupted in cancer.