Although inhibitory mechanisms that safeguard cells against DNA damages occur in all cells, genetic instability is widely present throughout living world. Some well known viruses cause alterations in host genome, leading to the formation of malignant transformations. Throughout this review we discuss some forms of instabilities caused by herpes simplex virus. Herpes simplex virus may induce chromosomal instabilities by various mechanisms, such as by formation of syncytium or ICP0-induced degradation of constitutive centromere proteins as well as may induce accumulation of point mutations by means of oxidative stress in neurons. We believe that further investigation of the ability of herpes simplex virus to cause genetic instability may help us to increase our understanding about the nature of this phenomenon.