Maintenance of genome integrity is essential for the proper function of all cells and organisms. In response to both endogenous and exogenous DNA damaging agents, mammalian cells have evolved a delicate system to sense DNA damage, stop cell cycle progression, modulate cell metabolism, repair damaged DNA, and induce programmed cell death if the damage is too severe. This coordinated global signaling network, namely the DNA damage response (DDR), ensures the genome stability under DNA damaging stress. A variety of regulators have been shown to modulate the activity and levels of key proteins in the DDR, including kinases, phosphatases, ubiquitin ligases, deubiquitinases, and other protein modifying enzymes. Epigenetic regulators, particularly microRNAs and long noncoding RNAs, have been emerging as an important payer of regulation in addition to canonical DNA damage signaling proteins. In this review, we will discuss the functional interaction between the regulators and their targets in the DDR.