Recent studies have identified, hSMG-1 as the newest member of the phosphoinositide 3-kinase(PI3-kinase)-related kinase (PIKK) family. The protein kinase activity of hSMG-1 resembles that of the related PIKK, ATM, both in terms of substrate specificity and its sensitivity to inhibition by the fungal metabolite wortmannin. hSMG-1 is the ortholog of a Caenorhabditis elegans protein, CeSMG-1, which has been genetically linked to a critical mRNA surveillance pathway termed nonsense-mediated decay (NMD). The function of NMD is to mark for rapid degradation mRNAs that bear a premature termination codon. Compelling evidence now indicates that hSMG-1 is also a central player in the NMD pathway in human cells. In addition, hSMG-1, like ATM, appears to be involved in the recognition and/or repair of damaged DNA in these cells. In this review, we introduce a model in which hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells.