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Resistance to viruses is an important aspect of plant breeding. Genetic resistance to viruses through loss of susceptibility has been selected in many crops. Among these resistances, translation initiation factors 4E (eIF4E) play a predominant role. In this article, we present a review of the research carried out on genes encoding translation initiation factors eIF4E, some of the most successful targets for obtaining resistance to potyviruses, since their characterization twenty years ago. With examples from different plant species (pepper, tomato, tobacco, and Arabidopsis), we present the foundations of this type of resistance and its characteristics, highlighting the role of gene redundancy among 4E factors, their virus specificity, and the necessary trade-off in plants between resistance and development. Finally, we show how the new genome-editing techniques could be used in plant breeding to develop eIF4E-based resistances in crops, by mimicking the functional alleles that have been selected during evolution in many crops.