The initiation of mRNA translation plays a pivotal role in gene expression and has profound implications for tumorigenesis, tumor progression, and drug resistance. eIF4F complex, as an important part of the classical translation initiation mechanism, has been widely studied in tumors, and tumor cells use it to enhance overall protein synthesis while while targeting the translation of oncogenes. In addition, the roles of a number of other translation initiation factors and translation initiation-related pathways (such as mTOR) in tumorigenesis and development have also been gradually discovered. Previous reports have shown that dysregulated translation initiation could enable tumor cells to thrive in challenging environments, such as hypoxia. These intricate processes are essential for adapting to complex circumstances and transforming the tumor immune microenvironment. This transformation equips cancer cells with the ability to evade detection by the immune system. Moreover, the dysfunction of translation initiation may cause drug resistance among tumors. This disruption increases the production of specific proteins that act as essential support systems for cancer cells, which enables them to withstand the adverse effects of various cancer treatments and increases the challenges in combating the disease. In this review, we examine the significance of translation initiation regulation in tumorigenesis and cancer development and highlight how abnormalities in translation initiation can cause drug resistance in tumors. We also evaluate the feasibility of developing combination therapies that target translation initiation in conjunction with other anticancer agents.