Herpes stromal keratitis (HSK) is a significant inflammatory disease of the cornea as a result of herpes simplex virus (HSV) infection often progressing to vision loss if left untreated. However, even with immunosuppressive compounds and anti-viral drug treatment, HSV continues to be the leading cause of infectious corneal blindness in the industrialized world. The inflammatory nature of the disease is the root of the pathogenic process characterized by irreversible corneal scarring, neovascularization of the avascular cornea, and infiltration of activated leukocytes. Experimental evidence using mice suggest HSK is the result of either molecular mimicry or a bystander activation phenomenon. This review will revisit the basis of HSK focusing on issues that pertain to the autoimmune component versus collateral damage as a result of non-specific activation as a means to explain the pathologic manifestations of the disease.