The continuous threats on genome integrity by endogenous and exogenous sources have rendered cells competent to overcome these challenges by activating DNA repair pathways. A complex network of proteins and their modifications participate in orchestrated signaling cascades, which are induced in response to DNA damage and may determine the choice of repair pathway. In this review, we summarize recent findings in the field of DNA Double Strand Break repair with regard to the positioning of the break in the highly compartmentalized nucleus. We aim to highlight the importance of chromatin state along with the nuclear position of the DNA lesions on the choice of DNA repair pathway and maintenance of genome integrity.