Significance: Double-stranded DNA breaks pose a serious threat to the survival of cells. Nonhomologous end joining (NHEJ) is a crucial DNA repair pathway in which the DNA-dependent protein kinase (DNA-PK) complex, a key holoenzyme consisting of the Ku70/80 heterodimer and the catalytic subunit DNA-PKcs, senses DNA breaks and initiates the NHEJ repair pathway. Here, we present cryo-EM structures of the DNA-PK complex. Together with previous structural and biochemical studies, our structures lead to a partial model for the interactions between DNA-PKcs and the Ku70/80 complex, and reveal how the DNA-PK complex may bring free ends of damaged DNA for repair.