Replication, transcription, and translation stress all lead to stalling of their respective polymerases (DNA polymerase, RNA polymerase, and the ribosome), and the cell must respond to these events in order to preserve macromolecular integrity. In response to replication stress such as DNA damage, the cell activates a checkpoint and promotes repair or bypass at the lesion. Transcriptional stress leading to stalling of RNA polymerase can also be caused by DNA damage, and recognizing stalled RNA polymerase can lead to transcription-coupled repair or, in response to prolonged stalling, degradation of the polymerase. Translational stress generated by problems either with the mRNA template or the ribosome itself also leads to stalling of the ribosome, and the cell responds by degrading both the message and the nascent polypeptide. In this review, we will discuss the stresses that lead to stalling of each of the polymerases and how the cell recognizes and responds to the stalled enzymes.