Colorectal cancers (CRC) are one of the most common causes of morbidity and mortality in high-income countries. Targeted screening programs have resulted in early treatment and a substantial decrease in mortality. However, treatment strategies for CRC still require improvement. Understanding the etiology and pathogenesis of CRC would provide tools for improving treatment of patients with this disease. It is only recently that deregulation of the protein synthesis apparatus has begun to gain attention as a major player in cancer development and progression. Among the numerous steps of protein synthesis, deregulation of the process of translation initiation appears to play a key role in cancer growth and proliferation. This manuscript discusses a fascinating and rapidly growing field exploring translation initiation as a fundamental component in CRC development and progression and summarizing CRC treatment perspectives based on agents targeting translation initiation.