Interruption of chromosomal integrity by DNA double-strand breaks (DSBs) causes a major threat to genomic stability. Despite tremendous progress in understanding the genetic and biochemical aspects of DSB-induced genome surveillance and repair mechanisms, little is known about organization of these molecular pathways in space and time. Here, we outline the key spatio-temporal problems associated with DSBs and focus on the imaging approaches to visualize the dynamics of DSB-induced responses in mammalian cells. We delineate benefits and limitations of these assays and highlight the key recent discoveries where live microscopy provided unprecedented insights into how cells defend themselves against genome-destabilizing effects of DNA damage.