Elsevier established a free COVID-19 resource center in January 2020, offering English and Mandarin information on the virus. The center is hosted on Elsevier Connect, a public news and information website. Elsevier grants permission to make all its COVID-19-related research freely available in PubMed Central and other public repositories for unrestricted reuse and analysis, with acknowledgment of the original source. The article discusses the scanning mechanism for translation initiation in eukaryotic mRNAs, where the 5' end plays a dominant role in identifying the start codon. Mutations creating upstream AUG codons can shift translation to these sites. Two mechanisms, reinitiation and context-dependent leaky scanning, allow downstream AUG codons to be accessed in some mRNAs. These mechanisms enable translation to occur even in extreme cases, such as a plant virus mRNA with three start sites over 900 nt. However, such structural arrangements are rare in cellular mRNAs. Understanding the rules of translation initiation helps explain human diseases where gene expression is reduced by mutations adding upstream AUG codons or altering the context around the AUG START codon. Conversely, mutations in thrombopoietin mRNA can increase translational efficiency, leading to overproduction of the cytokine and hereditary thrombocythemia. These examples show that 5' leader sequences are sometimes structured to control translation and prevent harmful overproduction of regulatory proteins. The scanning mechanism dictates the pattern of transcription, forcing production of monocistronic mRNAs and influencing the translation of eukaryotic cellular and viral genes. The article reviews the scanning mechanism, its implications for gene expression, and the role of reinitiation and leaky scanning in translation initiation. It also discusses the importance of context in determining the efficiency of translation initiation and the challenges posed by upstream AUG codons and secondary structures in the 5' untranslated region. The review highlights the complexity of translation initiation and the need for careful structural arrangements to ensure proper protein synthesis.Elsevier established a free COVID-19 resource center in January 2020, offering English and Mandarin information on the virus. The center is hosted on Elsevier Connect, a public news and information website. Elsevier grants permission to make all its COVID-19-related research freely available in PubMed Central and other public repositories for unrestricted reuse and analysis, with acknowledgment of the original source. The article discusses the scanning mechanism for translation initiation in eukaryotic mRNAs, where the 5' end plays a dominant role in identifying the start codon. Mutations creating upstream AUG codons can shift translation to these sites. Two mechanisms, reinitiation and context-dependent leaky scanning, allow downstream AUG codons to be accessed in some mRNAs. These mechanisms enable translation to occur even in extreme cases, such as a plant virus mRNA with three start sites over 900 nt. However, such structural arrangements are rare in cellular mRNAs. Understanding the rules of translation initiation helps explain human diseases where gene expression is reduced by mutations adding upstream AUG codons or altering the context around the AUG START codon. Conversely, mutations in thrombopoietin mRNA can increase translational efficiency, leading to overproduction of the cytokine and hereditary thrombocythemia. These examples show that 5' leader sequences are sometimes structured to control translation and prevent harmful overproduction of regulatory proteins. The scanning mechanism dictates the pattern of transcription, forcing production of monocistronic mRNAs and influencing the translation of eukaryotic cellular and viral genes. The article reviews the scanning mechanism, its implications for gene expression, and the role of reinitiation and leaky scanning in translation initiation. It also discusses the importance of context in determining the efficiency of translation initiation and the challenges posed by upstream AUG codons and secondary structures in the 5' untranslated region. The review highlights the complexity of translation initiation and the need for careful structural arrangements to ensure proper protein synthesis.