ETF1 (eukaryotic translation termination factor 1) is the primary component of the eRF1-eRF3-GTP ternary complex, which mediates translation termination in response to stop codons. ETF1 recognizes stop codons in the ribosomal A-site and catalyzes peptidyl-tRNA hydrolysis to release the completed polypeptide chain. Beyond canonical termination, ETF1 participates in nonsense-mediated mRNA decay (NMD) through its association with the SURF complex, which recruits quality-control factors to stalled ribosomes, and it regulates programmed ribosomal frameshifting mechanisms essential for viral and cellular gene expression. Recent therapeutic strategies have emerged targeting ETF1 to suppress premature termination codons: SRI-41315 reduces eRF1 abundance to enhance readthrough of cystic fibrosis transmembrane conductance regulator (CFTR) nonsense mutations, while photoreactive small-molecule probes that bind ETF1 inhibit SARS-CoV-2 and other viral replication by modulating frameshifting without causing protein degradation. ETF1 dysregulation associates with multiple malignancies; a KDM3B-ETF1 fusion gene identified in breast cancer promotes invasive ductal carcinoma progression through WNT/β-catenin pathway activation, and hemizygous loss of ETF1 occurs in myelodysplastic syndromes and acute myeloid leukemia with chromosome 5 deletions, though inactivating mutations in the remaining allele were not detected in studied samples.