It is emerging that the pathways that process newly transcribed RNA molecules also regulate the response to DNA damage at multiple levels. Here, we discuss recent insights into how RNA processing pathways participate in DNA damage recognition, signaling, and repair, selectively influence the expression of genome-stabilizing proteins, and resolve deleterious DNA/RNA hybrids (R-loops) formed during transcription and RNA processing. The importance of these pathways for the DNA damage response (DDR) is underscored by the growing appreciation that defects in these regulatory connections may be connected to the genome instability involved in several human diseases, including cancer.