Mus81-Mms4 is a DNA structure-specific endonuclease that has been implicated in meiotic recombination and processing of damaged replication forks in fungi. This work describes the generation and characterization of mus81 and mms4 mutations in Drosophila and investigation of the relationship of the MUS81-MMS4 endonuclease to the DmBlm helicase. Although Mus81 is involved in meiotic recombination in fungi, this role does not appear to be conserved in Drosophila. My finding that mus81 mutants are hypersensitive to agents that block or damage replication forks supports a role for MUS81-MMS4 in replication-fork repair. I found that null mutations in mus81 and mus309 exhibit synthetic lethality, which is associated with elevated apoptosis in proliferating tissues. Lethality and elevated apoptosis were partially suppressed by mutation in spn-A, which encodes DmRad51. I hypothesize that inability to repair endogenous DNA damage in the absence of MUS81 and DmBlm causes cell death ultimately leading to organismal death.