A group of inflammatory encephalopathies or encephalomyelopathies have been recognized in several toy breeds, including the Pug Dog, Chihuahua, Maltese Terrier, Pekingese, Yorkshire terrier and Pomeranian. These disorders are classified under the names necrotizing encephalitis (NE), necrotizing meningoencephalitis (NME) and granulomatous meningoencephalitis (GME). The most common of these disorders, NME in Pug Dogs or Pug Dog Encephalitis (PDE), affects 1-2% of individuals in the breed, and clinical signs with diagnostic features have been well documented over the last three decades. The cause of NME in Pug Dogs, however, has long been a point for speculation. The disorder was originally thought to have a viral etiology, but sensitive tools like the polymerase chain reaction (PCR) have failed to demonstrate viruses, viral particles, DNA or RNA in diseased tissues. A whole genome scan identified a single, strong association implicated a regions on CFA12, and fine mapping strongly implicated involvement of the class II genes, DRB1, DQA1, and DQB1. Sequencing of these three genes confirmed the importance of homozygosity for a specific allele at each locus, creating a specific haplotype found almost exclusively in Pug Dogs with NME. Given the strong DLA class II gene association in Pug Dogs with NME, a similar genetic relationship was sought for other toy breeds suffering from NME and/or GME. Homozygosity in the DLA class II genes, but in no specific allele, was found to be associated to some extent with GME in Maltese Terriers. However, neither homozygosity nor a specific allele appeared to be related to these disorders in Chihuahuas, Pekingese, and Pomeranians. However, the numbers of affected and non-affected dogs of these non-Pug Dog breeds was relatively small and the findings need to be confirmed with a larger cohort of normal and affected animals. These preliminary findings suggest that immune encephalopathies in various toy breeds are similar in clinical form but have different genetic bases.