Feline coronaviruses (FCoVs) are the causative agent of feline infectious peritonitis (FIP), which is a lethal disease of cats. FCoVs exists as two distinct serotypes (the more common type I, as well as type II viruses), and two distinct biotypes. One biotype, feline enteric coronavirus (FECV) is common in cats, infects enterocytes in the gastro-intestinal tract and causes only mild disease. The second biotype, feline infectious peritonitis virus (FIPV) infects macrophages, spreads systemically and causes FIP in approximately 1-5% of FCoV-infected cats. Both serotypes of FCoV can cause FIP. A long-standing hypothesis has been that lethal FIPVs derive from benign FECVs by a process of “internal mutation”. Our laboratory has provided strong support for the internal mutation hypothesis, and has recently shown that mutations in the proteolytic cleavage site(s) of the FCoV spike protein strongly correlates with the development of FIP in cats. Overall, we have identified a complex pattern of mutation at the spike cleavage sites that is currently being validated for use as a PCR/sequencing-based FIP diagnostic test.