Varicella-zoster virus (VZV) is well known for its propensity to cause polykaryons (syncytia) in the vesicles within infected skin. Similarly in cultured cells, VZV induces extensive syncytial formation by virus-mediated cell-to-cell fusion. Statistical analyses of fusion parameters demonstrated three-way interactive effects among all three tested variables (incubation temperature, cell type and virus strain). For example, fusion was greatly enhanced at 33°C vs 37°C; also fusion was pronounced in epidermal cells but negligible in fibroblast cells. As with all herpesviruses, VZV gH was a major fusogen. VZV cell fusion was inhibited by antibody to gH, but surprisingly was enhanced by antibody to gE. Other evidence implicating a role for VZV gE in the fusion process was provided by two mutant viruses, in which gE cell surface expression was enhanced. Under transfection conditions, VZV fusion formation occurred after expression of the gH/gL complex; in contrast, pseudorabies virus requires expression of gH, gL and gB, while the herpes simplex virus (HSV) types 1 and 2 require the quartet of gH, gL, gB and gD. VZV has no gD gene and no apparent gD functional homologue. On the other hand, VZV gE exerts a greater effect than HSV gE on membrane fusion. Taken together, the data in this review suggest that VZV has evolved viral glycoprotein machinery more geared toward cell-to-cell fusion (fusion-from-within) than toward virus-to-cell fusion (entry/fusion-from-without), as a means for syncytium formation within the human epidermis. Copyright © 2003 John Wiley & Sons, Ltd.