Duplication of the eukaryotic genome occurs in the context of a chromatin template that is actively engaged in regulating gene expression and other protein-DNA interactions. Chromatin structures influence the dynamics of DNA replication by regulating the selection of replication origin sites as well as the initiation timing of the selected origins. Recent studies indicate that active origins frequently localize with active or potentially active gene promoters, suggesting coordination of these fundamental DNA transactions. The coordination of replication and transcription has been implicated as a mechanism for the establishment and inheritance of differential gene expression patterns during cellular differentiation. Here we consider the possible impact of coordinating replication with transcription for promoting the efficiency of both processes, and for protecting genome stability. In particular, we discuss mechanisms through which proper temporal and spatial coordination of replication and transcription serve to minimize head-on collisions of the transcription and replication machineries, which have been associated with genomic instabilities. We also discuss future research directions that should lead to a better understanding of these mechanisms and their significance to faithful genome propagation and cellular differentiation.