The article provides an overview of the mechanisms of translation initiation in eukaryotic cells, focusing on the role of internal ribosome entry sites (IRESs) in certain viral and cellular mRNAs. Most eukaryotic mRNAs initiate translation by 5′-end-dependent recruitment of the 40S ribosomal subunit, which scans the mRNA until it encounters an appropriate start codon. However, a subset of mRNAs contains IRESs, which enable end-independent initiation. The authors discuss the molecular mechanisms of IRES-mediated initiation, including ribosomal shunting and internal initiation, and how these mechanisms allow translation to occur under specific physiological conditions such as mitosis, apoptosis, hypoxia, and viral infections. They also detail the discovery and characterization of IRES elements in picornaviruses, hepatitis C virus, and cricket paralysis virus, highlighting the unique structural features and regulatory requirements of these elements. The article emphasizes the importance of RNA secondary structure and specific RNA-binding proteins in mediating IRES function and the diverse mechanisms by which IRESs can recruit ribosomes to initiate translation.The article provides an overview of the mechanisms of translation initiation in eukaryotic cells, focusing on the role of internal ribosome entry sites (IRESs) in certain viral and cellular mRNAs. Most eukaryotic mRNAs initiate translation by 5′-end-dependent recruitment of the 40S ribosomal subunit, which scans the mRNA until it encounters an appropriate start codon. However, a subset of mRNAs contains IRESs, which enable end-independent initiation. The authors discuss the molecular mechanisms of IRES-mediated initiation, including ribosomal shunting and internal initiation, and how these mechanisms allow translation to occur under specific physiological conditions such as mitosis, apoptosis, hypoxia, and viral infections. They also detail the discovery and characterization of IRES elements in picornaviruses, hepatitis C virus, and cricket paralysis virus, highlighting the unique structural features and regulatory requirements of these elements. The article emphasizes the importance of RNA secondary structure and specific RNA-binding proteins in mediating IRES function and the diverse mechanisms by which IRESs can recruit ribosomes to initiate translation.