Appropriate cellular signaling responses to DNA damage and the ability to repair DNA are fundamental processes that are required for organismal survival. Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease that results from defective DNA damage signaling. Understanding the molecular basis of A-T has provided many critical insights into the cellular response to DNA double-strand breaks (DSBs). A-T is a syndrome that shows pronounced neurodegeneration of the nervous system coincident with immune deficiency, radiosensitivity, and cancer proneness. A-T results from inactivation of the A-T mutated (ATM) kinase, a critical protein kinase that regulates the response to DNA-DSBs by selective phosphorylation of a variety of substrates. Therefore, understanding the ATM signaling program has important biological ramifications for nervous system homeostasis. Underscoring the importance of the DNA-DSBs response in the nervous system are other diseases related to A-T that also result from defects in this signaling pathway. In particular, defects in the DNA damage sensor, the Mre11-RAD50-NBS1 complex, also lead to syndromes with neurological deficits and overlapping phenotypes to A-T. Collectively, these diseases highlight the critical importance of appropriate responses to DNA-DSBs to maintain homeostasis in the nervous system.