Members of the Herpesviridae family of viruses are classified into the alpha, beta and gamma subfamilies. The alpha subfamily is estimated to have diverged from the beta and gamma subfamilies 200-220 million years ago. The ancestors of the herpes simplex virus (HSV) and the varicella-zoster virus (VZV), two ubiquitous and clinically important human pathogens, appeared 70-80 million years ago. As these viruses coevolved with their specific primate hosts, genetic rearrangements led to the development of the contemporary alphaherpesviruses and their distinct complement of genes. Here the distinct features of HSV and VZV are discussed in terms of their transmissibility, clinical picture, tissue tropism, establishment of latency/reactivation and immune evasion, which can, at least in part, be explained by differences in their genomes.