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ATM (Ataxia Telangiectasia Mutated) is a serine/threonine protein kinase best known for its role in the DNA damage signaling cascade in response to DNA double-strand breaks (DSBs). When DSBs occur, the MRE11:RAD50:NBS1 (MRN) sensor complex recruits ATM to the sites of DNA damage. ATM then signals to numerous effector proteins, leading to cellular responses that include the regulation of DNA repair, cell cycle progression, apoptosis, senescence, and gene transcription. Together with ATR, DNA-PKcs, SMG1, and mTOR, ATM is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, which typically responds to various types of cellular stress. ATM has many substrates, including CHK2, AKT, p53, BRCA1, and DNA-PK. Inactive ATM exists as a dimer. In response to DSBs, ATM undergoes trans-autophosphorylation at Ser1981, leading to the dissociation of the complex into active monomers. Functional DNA repair pathways are important for cellular homeostasis, and defects in these pathways can lead to genomic instability and tumorigenesis. Inactivation of ATM leads to ataxia telangiectasia (AT), a neurodegenerative disorder characterized by cancer predisposition.