Copyright © 2015 Elsevier Inc. All rights reserved.
It is commonly assumed that there is a single canonical DNA damage response (DDR) that protects cells from various types of double-strand breaks and that its activation occurs via recognition of DNA ends by the DDR machinery. Recent work suggests that both assumptions may be oversimplifications. Here, we discuss several variations of the DDR in which the pathway is activated by diverse cellular events and/or generates distinct signaling outcomes. The existence of multiple non-canonical DDRs provides insights into how DNA damage is sensed and suggests a highly modular organization of the DDR.