DNA strand breaks are potentially mutagenic and must, therefore, be recognized and repaired. Recent work has identified DNA polymerase epsilon, Ku, and proteins such as DNA-PKcs, Mec1 and Tel1 as key players in DNA damage recognition pathways. Studies on these and other factors have provided important insights into the mechanisms of DNA repair and how DNA damage signals are transduced to the transcription and cell cycle machineries. This work also suggests how deficiencies in DNA damage detection systems can result in genetic instability and cancer.