Viruses exhibit a marked variation in their susceptibilities to chemical and physical inactivation. Identifying a trend within these variations, if possible, could be valuable in the establishment of an effective and efficient infection control or risk mitigation strategy. It has been observed that non-enveloped viruses are generally less susceptible than enveloped viruses and that smaller sized viruses seem less susceptible than larger viruses. A theory of a “hierarchy” of pathogen susceptibility has been proposed and widely referenced. This concept provides a useful general guide for predicting the susceptibility of a newly emerged pathogen. It also serves as a theoretical basis for implementing a limited scale viral inactivation study that is to be extrapolated onto many other viruses. The hierarchy concept should be interpreted with caution since the actual viral inactivation efficacy may, in some cases, be different from the general prediction. The actual efficacy is dependent on the type of chemistry and application conditions. The order of susceptibility is not always fixed; and viruses within the same family or even the same genus may exhibit drastic differences. This chapter reviews viral inactivation data for several commonly used chemistries against non-enveloped viruses, highlighting the cases wherein the order of susceptibility varied or even flipped. Possible underlying mechanisms are also discussed.