<p>Transcription–replication conflicts (TRCs) arise when DNA replication forks encounter actively transcribing RNA polymerases, creating a major threat to genome stability. These conflicts, which can occur in different orientations, disrupt replication fork progression, impair transcriptional fidelity and reshape the chromatin landscape. In this review, we discuss emerging conceptual insights into how cells coordinate replication and transcription in space and time to minimise such encounters, and we highlight the central role of RNA polymerase II dynamics in both preventing and resolving TRCs. We further describe how TRCs engage a broad network of genome maintenance pathways that regulate R-loops, stabilize stalled forks and maintain chromatin integrity. Importantly, elevated or mismanaged TRCs create vulnerabilities that many cancers exploit, positioning conflict-resolution mechanisms as attractive therapeutic targets. Finally, we examine current challenges in detecting and analysing these transient, dynamic events and underscore the need for improved imaging and sequencing technologies to study the genome’s molecular “traffic jams”. A deeper mechanistic understanding of TRCs will be crucial for harnessing them in precision oncology and clarifying their broader roles in genome regulation.</p>