The two VZV glycoproteins, gE and gI, are encoded by genes that are designated open reading frames, ORF67 and ORF68, located in the short unique region of the VZV genome. These proteins have homologs in the other alphaherpesviruses. Like their homologues, VZV gE and gI exhibit prominent co-localization in infected cells and form heterodimers. However, VZV gE is much larger than its homologues because it has a unique N-terminal domain, consisting of 188 amino acids that are not present in these other gene products. VZV gE also differs from the related gE proteins, in that it is essential for viral replication. Targeted mutations of gE that are compatible with VZV replication in cultured cells have varying phenotypes in skin and T-cell xenografts in the SCID mouse model of VZV pathogenesis in vivo. While gI is dispensable for growth in cultured cells in vitro, this glycoprotein is essential for VZV infection of differentiated human skin and T cells in vivo. The promoter regions of gE and gI are regulated by the cellular transactivator, specificity protein factor 1 (Sp1) in combination with the major VZV transactivator in reporter construct experiments and some Sp1 promoter elements are important for VZV virulence in vivo. Further analysis of VZV gE and gI functions and their interactions with other viral and host cell proteins are important areas for studies of VZV replication and pathogenesis.