DNA and RNA polymerases clash along the genome as they compete for the same DNA 
template. Cells have evolved specialized strategies to prevent and resolve 
replication and transcription interference. Here, we review the topology and 
architecture at sites of replication fork clashes with transcription bubbles as 
well as the regulatory circuits that control replication fork passage across 
transcribed genes. In the case of RNA polymerase II-transcribed genes, 
cotranscriptional processes such as mRNA maturation, splicing, and export 
influence the integrity of replication forks and transcribed loci. Fork passage 
likely contributes to reset the epigenetic landscape, influencing gene 
expression and transcriptional memory. When any of these processes are not 
properly coordinated, aberrant outcomes such as fork reversal and R-loop 
formation arise and trigger unscheduled recombinogenic events and genome 
rearrangements. The evolutionary implications of such conflicts on genome 
dynamics and their potential impact on oncogenic stress are discussed.