Living organisms have to protect the integrity of their genomes in order to survive. A mechanism called the DNA damage response was developed during evolution to ensure the maintenance of genome integrity. Damage to DNA induces several cellular responses, including the repair of DNA lesions, the activation of cell cycle checkpoints, and cell death if the damage is not repaired. In this review, we first summarize known features of the DNA damage response, emphasizing those elements that function as sensors of DNA damage, transducers of the damage signal, or effectors that mediate the response. Subsequently, we focus on aspects of the fungal DNA damage response that distinguish it from the well-characterized yeast models. These include the characterization of conserved repair proteins that first appear in the multicellular fungi, the potential role of hyphal cell death in the fungal DNA damage response, the challenge of regulating the response in a multinucleate cell, and the novel interaction between cell cycle checkpoints and hyphal morphogenesis. Although, in some cases, our analyses may be somewhat speculative, we propose that these aspects of the fungal DNA damage response may serve as valuable models that yield important insight into analogous processes in other multicellular eukaryotes.