For many years it has been evident that mammalian cells differ dramatically from yeast and rejoin the majority of their DNA DSBs by a nonhomologous mechanism, recently termed NHEJ. In the last few years a number of genes and proteins have been identified that operate in the pathway providing insights into the mechanism. These proteins include the three components of DNA-PK, DNA ligase IV, and XRCC4. In yeast Sir2, -3, and -4 proteins are also involved in the process and therefore are likely to play a role in higher organisms. Studies with yeast suggest that NHEJ is an error-free mechanism. Although the process is far from understood, it is likely that the DNA-PK complex or Ku alone acts in a complex with the Sir proteins possibly protecting the ends and preventing random rejoining. Further work is required to establish the details of this mechanism and to determine whether this represents an accurate rejoining process for a complex break induced by ionizing radiation. It will be intriguing to discover how the cell achieves efficient and accurate rejoining without the use of homology. Interactions between the components of DNA-PK and other proteins playing a central role in damage response mechanisms are beginning to emerge. Interestingly, there is evidence that DNA repair and damage response mechanisms overlap in lower organisms. The overlapping defects of the yeast Ku mutants, tell mutants, and AT cell lines in telomere maintenance further suggest overlapping functions or interacting mechanisms. A challenge for the future will be to establish how these different damage response mechanisms overlap and interact.