During the last decades it has been shown that the replication timing program in metazoans is related to chromosome structure, the nuclear positioning and AT/GC content of chromosomal loci, their patterns of histone modifications, and their transcriptional regulation. Here, the current state of knowledge concerning these relationships is reviewed. An integrated view on structure-function relationships in the nucleus is provided and the determination and functional role of the replication timing program is discussed in this context. A corresponding comprehensive model is developed and a key aspect of this model is the suggestion that mammalian chromosomes are organized into stable units equivalent to replicon clusters. It is proposed that the nuclear positions of these units would depend on their histone modifications and determine the replication timing of the whole unit. It is furthermore predicted that replication timing is only indirectly linked to transcriptional regulation and contributes to the maintenance of gene expression patterns. These clear predictions, and the fact that the tools are at hand now to further test them, open an avenue towards solving the long standing problem on how replication timing is determined in metazoan cells.