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Eukaryotic mRNAs were historically thought to rely exclusively on recognition and binding of their 5′ cap by initiation factors to effect protein translation. While internal ribosome entry sites (IRESs) are well accepted as necessary for the cap-independent translation of many viral genomes, there is now recognition that eukaryotic mRNAs also undergo non-canonical modes of translation initiation. Recently, high-throughput assays have identified thousands of mammalian transcripts with translation initiation occurring at non-canonical start codons, upstream of and within protein coding regions. In addition to IRES-mediated events, regulatory mechanisms of translation initiation have been described involving alternate 5′ cap recognition, mRNA sequence elements, and ribosome selection. These mechanisms ensure translation of specific mRNAs under conditions where cap-dependent translation is shut down and contribute to pathological states including cardiac hypertrophy and cancer. Such global and gene-specific dynamic regulation of translation presents us with an increasing number of novel therapeutic targets. While these newly discovered modes of translation initiation have been largely studied in isolation, it is likely that several act on the same mRNA and exquisite coordination is necessary to maintain ‘normal’ translation. In this short review, we summarize the current state of knowledge of these alternative mechanisms of eukaryotic protein translation, their contribution to normal and pathological cell biology, and the potential of targeting translation initiation therapeutically in human disease.