Regulation of translation initiation is a central control point in animal cells. We review our current understanding of the mechanisms of regulation, drawing particularly on examples in which the biological consequences of the regulation are clear. Specific mRNAs can be controlled via sequences in their 5′ and 3′ untranslated regions (UTRs) and by alterations in the translation machinery. The 5′UTR sequence can determine which initiation pathway is used to bring the ribosome to the initiation codon, how efficiently initiation occurs, and which initiation site is selected. 5′UTR-mediated control can also be accomplished via sequence-specific mRNA-binding proteins. Sequences in the 3′ untranslated region and the poly(A) tail can have dramatic effects on initiation frequency, with particularly profound effects in oogenesis and early development. The mechanism by which 3′UTRs and poly(A) regulate initiation may involve contacts between proteins bound to these regions and the basal translation apparatus. mRNA localization signals in the 3′UTR can also dramatically influence translational activation and repression. Modulations of the initiation machinery, including phosphorylation of initiation factors and their regulated association with other proteins, can regulate both specific mRNAs and overall translation rates and thereby affect cell growth and phenotype.