Kinases in the phosphoinositide three-kinase-related kinase (PIKK) family include ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related), DNA-PKcs (DNA-dependent protein kinase catalytic subunit), mTOR (mammalian target of rapamycin), and SMG1 (suppressor with morphological effect on genitalia family member). These atypical protein kinases regulate DNA damage responses, nutrient-dependent signaling, and nonsense-mediated mRNA decay. This review focuses on the mechanisms regulating the PIKK family with a strong emphasis on the DNA damage regulated kinases. We outline common regulatory themes and suggest how discoveries about the regulation of one PIKK can be informative for the other family members.