DNA repair is a critical cellular process required for the maintenance of genomic integrity. It is now well appreciated that cells employ several DNA repair pathways to take care of distinct types of DNA damage. It is also well known that a cascade of signals namely DNA damage response or DDR is activated in response to DNA damage which comprise cellular responses, such as cell cycle arrest, DNA repair and cell death, if the damage is irreparable. There is also emerging literature suggesting a cross-talk between DNA damage signaling and several signaling networks within a cell. Moreover, cell death players themselves are also well known to engage in processes outside their canonical function of apoptosis. This chapter attempts to build a link between DNA damage, DDR and signaling from the studies mainly conducted in mammals and Drosophila model systems, with a special emphasis on their relevance in overall tissue homeostasis and development.