The DNA damage response (DDR) system is critical to maintain genomic integrity and guard against DNA damages. DDR alterations, resulting from DDR gene mutations or epigenetic modifications, have been involved in cancer initiation, progression, and treatment response.However, the role of DDR alterations in cancer metastasis has not been well characterized.Recently, there is increasing evidence of an important role of DDR in regulating multiple facets of Note to the Reader: This chapter is part of the book Metastasis (ISBN: 978-0-6453320-2-5), scheduled for publication in April 2022. The book is being published by Exon Publications,