As DNA is frequently subject to a wide array of molecularly distinct forms of damage, life has evolved various DNA repair mechanisms and associated processes, collectively termed the DNA-damage response (DDR). The importance of DNA repair and DDR mechanisms is underlined by their deregulation or loss causing cancer and various human genetic disorders whose pathologies include stem-cell exhaustion, developmental defects, infertility, immune-deficiency, neurodegeneration and/or premature ageing. Work in my laboratory aims to decipher DDR mechanisms, particularly those triggered by DNA double-strand breaks. In this talk, I will describe some of our recent work combining CRISPR-based genome engineering and genetic screens with mechanistic studies to identify new DDR factors/regulators and define their functions, and to define and understand cross talks and functional interactions between DDR components. I will also explain how our work has identified new avenues for anti-cancer therapy and is helping us understand how cancer cells can evolve resistance to therapeutic agents.