Gross chromosome rearrangements (GCRs), such as translocations, deletion of a chromosome arm, interstitial deletions and inversions, are often observed in cancer cells. Spontaneous GCRs are rare in Saccharomyces cerevisiae; however, the existence of mutator mutants with increased genome instability suggests that GCRs are actively suppressed. Here we show by genetic analysis that these genome rearrangements probably result from DNA replication errors and are suppressed by at least three interacting pathways or groups of proteins: S-phase checkpoint functions, recombination proteins and proteins that prevent de novo addition of telomeres at double-strand breaks (DSBs). Mutations that inactivate these pathways cause high rates of GCRs and show synergistic interactions, indicating that the pathways that suppress GCRs all compete for the same DNA substrates.