After several decades during which nucleoside analogues (especially acyclovir and penciclovir and their prodrugs) have benefited many patients suffering from herpes simplex virus (HSV) infections, the discovery of the helicase-primase inhibitors (HPIs) represents an interesting new approach. Although antiviral resistance has not been a major problem for nucleoside analogues in immunocompetent patients, the problem of acyclovir resistance in immunocompromised patients is well documented. Several HPIs are extremely potent antiviral compounds and may, therefore, offer an important alternative therapy in these patients. The potential for synergy, not just for the inhibition of virus replication but also to delay the appearance of drug-resistant virus, needs to be thoroughly investigated. The study of resistance to HPIs has been important towards understanding the mechanism of action of these compounds and confirming the target function. However, during the course of our studies on HPI resistance, we have made a number of interesting observations that may be relevant to their clinical use. This article draws attention to the major observations on HPI resistance reported by others and to our own recently published observations that have extended this expanding area of antiviral research.