Myxomatous mitral valve disease (MMVD) is the most common heart disease and cause of cardiac death in domestic dogs. MMVD is characterised by slow progressive myxomatous degeneration from the tips of the mitral valves onwards with subsequent mitral valve regurgitation, and left atrial and ventricular dilatation. Although the disease usually has a long asymptomatic period, in dogs with severe disease, mortality is typically secondary to left-sided congestive heart failure. Although it is not uncommon for dogs to survive long enough in the asymptomatic period to die from unrelated causes; a proportion of dogs rapidly advance into congestive heart failure. Heightened prevalence in certain breeds, such as the Cavalier King Charles Spaniel, has indicated that MMVD is under a genetic influence. The genetic characterisation of the factors that underlie the difference in progression of disease is of strong interest to those concerned with dog longevity and welfare. Advanced genomic technologies have the potential to provide information that may impact treatment, prevalence, or severity of MMVD through the elucidation of pathogenic mechanisms and the detection of predisposing genetic loci of major effect. Here we describe briefly the clinical nature of the disorder and consider the physiological mechanisms that might impact its occurrence in the domestic dog. Using results from comparative genomics we suggest possible genetic approaches for identifying genetic risk factors within breeds. The Cavalier King Charles Spaniel breed represents a robust resource for uncovering the genetic basis of MMVD.