Initiation of translation of most eukaryotic mRNAs commences with 5 end–dependent recruitment of 40S ribosomal subunits to the mRNA. The 40S subunit carrying the initiator methionine-tRNA and certain eukaryotic initiation factors (eIFs) is thought to scan the mRNA in a 5 to 3 direction until an appropriate start codon is encountered at which stage a 60S subunit joins to form an 80S ribosome that can decode the RNA into protein (Kozak 1989; Hershey and Merrick 2000). A subset of mRNAs contains internal ribosomal entry sites (IRESs), usually in the 5 NTR, that enable end-independent initiation to occur. IRES-containing mRNAs are not subjected to many of the regulatory mechanisms that control recruitment of most mRNAs to the translation apparatus. In this review, we briefly provide an introduction to the known mechanisms of translation initiation. Then, we discuss in detail the molecular mechanisms of IRES-mediated initiation and how they are used by specific mRNAs to permit translation under physiological circumstances such as mitosis, apoptosis, hypoxia, and some viral infections when translation of most mRNAs is repressed.