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Equid herpesviruses types 1 and 4 (EHV-1 and EHV-4) are closely related pathogens of horses. While both viruses can infect the upper respiratory tract, EHV-1 regularly causes systemic infection, which is only rarely observed in the case of EHV-4. Little is known about the molecular basis for this striking difference in pathogenic potential. Recently, we have started a systematic analysis of differences in the amino acid sequences of proteins involved in virus replication, more specifically entry and egress, as well as proteins involved in immune evasion. Here, we summarize our findings relevant to glycoproteins D and G (gD and gG), which share a high degree of similarity between the viruses, yet exhibit important differences. We found that both these glycoproteins appear to be involved in the conquest of the mononuclear cell compartment. While gD is involved in infection of peripheral blood mononuclear cells through an RSD motif present in EHV-1 but not EHV-4, gG is implicated in thwarting innate responses by sequestration of chemokines. Again, the activity is only present in EHV-1, more specifically in a short stretch of variable amino acids in the extracellular domain of gG. The differences in the two glycoproteins of EHV-1 and EHV-4 are discussed, as is their role in pathogenesis. In addition, hypotheses are proposed related to the other equid respiratory alphaherpesviruses, EHV-8 and EHV-9, based on the amino acid sequences of gD and gG.