The genome is under constant attack by self-produced reactive oxygen species and genotoxic reagents in the environment. Cells have evolved a DNA damage response (DDR) system to sense DNA damage, to halt cell cycle progression and repair the lesions, or to induce apoptosis if encountering irreparable damage. The best studied DDR pathways are the PIKK-p53 and PIKK-Chk1/2. Mutations in these genes encoding DDR molecules usually lead to genome instability and tumorigenesis. It is worth noting that there exist unconventional pathways that facilitate the canonical pathways or take over in the absence of the canonical pathways in DDR. This review will summarize on several unconventional pathways that participate in DDR with an emphasis on the BMP-Smad1 pathway, a known regulator of mouse development and bone remodeling. J. Cell. Biochem. 115: 450–456, 2014. © 2013 Wiley Periodicals, Inc.