Non-infectious meningoencephalomyelitis (NIME) presents clinicians with diagnostic problems because specific diagnosis requires histopathological examination of central nervous system (CNS) tissue. In the absence of a precise diagnosis, clinicians refer instead to 'meningoencephalomyelitis of unknown origin' (MUO). This article compares published data on histopathologically diagnosed disease (granulomatous meningoencephalomyelitis and necrotising encephalitis) with information available on the clinically-defined category of MUO. Small, middle-aged female dogs are most commonly affected by all types of NIME, but there is considerable overlap in diagnostic parameters of these diseases. Future clinical trials must aim to compare prospectively two or more randomly allocated treatments and to include pre-trial power calculations. This article provides the necessary background information to permit rational patient selection on clinical presentation alone, rather than requiring CNS biopsy, thus maximising patient recruitment whilst minimising heterogeneity.