(A) Canonical initiation involves the eIF4F complex and the poly(A) tail binding protein PABP binding to the mRNA and subsequently interacting with the 43S complex (eIF5, eIF3, eIF2 and the 40S ribosome) to form the 48S complex. eIF4E and PABP both interact with eIF4G to create a ‘closed loop complex'. eIF4A, with its cofactors eIF4B and eIF4H, interact with eIF4G and eIF4E to provide helicase activity to unwind secondary structures present in the 5′UTR. The 48S complex scans the mRNA for an AUG start codon, where the 60S ribosomal subunit is recruited through eIF5B and several of the initiator factors are displaced and recycled to initiate a new round of translation. (B) IRES mediated translation involves a strong secondary or tertiary structure within the 5′UTR. The precise mechanisms vary between viruses but the IRES element interacts with either the 40S subunit or eIF4G, which recruit any other required factors to initiate translation. (C) Canonical and alternative physiological initiator tRNA-binding eIF factors recognise different start codons. Canonical translation occurs through eIF2α, delivering Met-tRNA_i^Met to the P site of the 40S ribosomal subunit in a GTP-dependent manner, through interaction with both the canonical AUG start codon and near cognate start codons CUG and GCG. Both eIF2A and eIF2D are also able to initiate translation, however this can occur in a GTP-dependent or independent manner, binding either charged or uncharged tRNA_i^Met. eIF2A can additionally bind Leu-tRNA^CUG to initiate translation. eIF2A can initiate translation at AUG, CUG and UUG codons, while eIF2D can initiate at AUG, CUG, GCG and UUG codons.