Ionizing radiation causes a variety of types of damage to DNA in cells, requiring the concerted action of a number of DNA repair enzymes to restore genomic integrity. The DNA base-excision repair and DNA double-strand break repair pathways are particularly important. While single base damages are rapidly excised and repaired using the opposite (undamaged) strand as a template, the correct repair of DNA double-strand breaks may present more difficulties to cellular enzymes owing to the loss of template. In the last few years evidence in support of several enzymatic pathways for the repair of such double-stranded damage has been found. At present we may distinguish at least three pathways: homologous recombination repair, non-homologous (DNA-PK-dependent) end joining, and repeat-driven end joining. This paper focuses on evidence for the first and third of these pathways, and considers in particular their relative importance in mammalian cells and implications for the fidelity of repair.