Protein synthesis is a vital cellular process that regulates growth and metabolism. It is controlled via signaling networks in response to environmental changes, including the presence of nutrients, mitogens, or starvation. The phosphorylation state of proteins involved in translation initiation is a limiting factor that regulates the formation or activity of translational complexes. In cancer cells, hyperactivated signaling pathways influence translation, allowing uncontrolled growth and survival. In addition, several components of translation initiation have been found to be mutated, posttranslationally modified, or differentially expressed, and some act as oncogenes in cancer cells. Translational alterations can increase the overall rate of protein synthesis as well as activate regulatory mechanisms leading to the translation of specific messenger RNAs for proteins that promote cancer progression and survival. Many recent studies investigating such mechanisms have produced ideas for therapeutic intervention. This review describes altered mechanisms of protein synthesis in human cancers and discusses therapeutic approaches based on the targeting of translation. Cancer Res; 72(16); 3891–900. ©2012 AACR.