Tumorigenesis is known to result from multiple genetic changes. Although endogenous and environmental insults can damage DNA, cellular mechanisms exist to repair various forms of damage or to kill those cells irreparably damaged. Hence, the accumulation of numerous genetic changes that would lead to cancer in normal cells is extremely rare. Nevertheless, disruption of a DNA repair pathway has the potential to expedite tumorigenesis by resulting in a cell that is hypermutable. Multiple pathways exist to repair the various forms of DNA damage that can cause mutagenesis. Recent studies have demonstrated a key role for homologous recombination in DNA repair, in particular in the repair chromosomal double-strand breaks. This review summarizes those studies and discusses how disruption of homologous recombination pathways can create genetic instability.