Recent studies have shown that resistance in several dicotyledonous plants to viruses in the genus Potyvirus is controlled by recessive alleles of the plant translation initiation factor elF4E or elF(iso)4E genes. Here we provide evidence that the barley rym4 gene locus, controlling immunity to viruses in the genus Bymovirus, corresponds to elF4E. A molecular marker based on the sequence of elF4E was developed and used to demonstrate that elF4E and rym4 map to the same genetic interval on chromosome 3HL in barley. Another genetic marker was developed that detects a polymorphism in the coding sequence of elF4E and consistently distinguishes between rym4 and susceptible barley cultivars of diverse parentage. The elF4E gene product from barley genotypes carrying rym4 and allelic rym5 and rymb genes, originating from separate exotic germplasm, and a novel resistant allele that we identified through a reverse genetics approach all contained unique amino acid substitutions compared with the wild-type protein. Three-dimensional models of the barley elF4E protein revealed that the polymorphic residues identified are all located at or near the mRNA cap-binding pocket, similarly to recent findings from studies on recessive potyvirus resistance in dicotyledonous plants. These new data complement our earlier observations that specific mutations in bymovirus VPg are responsible for overcoming rym4/5-controlled resistance. Because the potyviral VPg is known to interact with elF4E in dicotyledonous plants, it appears that monocotyledonous and dicotyledonous plants have evolved a similar strategy to combat VPg-encoding viruses in the family Potyviridae.