Feline calicivirus (FCV) is a common feline pathogen associated with a variety of clinical syndromes. Typically, FCV infection is either asymptomatic or causes mild upper respiratory signs, oral ulceration, and fever; fatal disease is unusual. In 1998 however, an outbreak of atypical FCV caused severe systemic disease. Since that report, there have been multiple other documented outbreaks of extremely virulent FCV that have resulted in mortality rates as high as 50%. The extremely virulent nature of these viruses as well as the reported speed with which they can spread within veterinary hospitals and shelters makes their early identification imperative for limiting morbidity and mortality. Sequence analysis of the FCV structural protein did not identify conserved sequence unique to highly virulent viruses, suggesting highly virulent isolates have arisen independently. Analysis of FCV in vitro properties including growth kinetics and neutralization assays suggests a determinant of virulence in FCV is accelerated entry post-binding.