Three independent, fatal outbreaks of Streptococcus canis infection occurred in a 2-year period in shelter cats. The outbreaks occurred in Northern California (Yolo County), Southern California (Kern County), and North Carolina (Guilford County). An estimation of the affected population is >150 cats among 3 affected shelters, with a mortality rate of up to 30%. Among 20 cats submitted for necropsy there were 2 distinct pathologic presentations. The first (shelters 1 and 2) was skin ulceration and chronic respiratory infection that progressed, in some cats, to necrotizing sinusitis and meningitis. The second (shelter 3) was rapid progression from necrotizing fasciitis with skin ulceration to toxic shock-like syndrome, sepsis, and death. S canis was the sole pathogen identified in most cases. Whether hypervirulent S canis strains exist is unknown; there is little understanding of how these bacteria cause invasive disease in cats.