Neurodegenerative disorders are characterized by the formation of distinct pathological changes in the brain, including extracellular protein deposits, cellular inclusions, and changes in cell morphology. Since the earliest published descriptions of these disorders, diagnosis has been based on clinicopathological features, namely, the coexistence of a specific clinical profile together with the presence or absence of particular types of lesion. In addition, the molecular profile of lesions has become an increasingly important feature both in the diagnosis of existing disorders and in the description of new disease entities. Recent studies, however, have reported considerable overlap between the clinicopathological features of many disorders leading to difficulties in the diagnosis of individual cases and to calls for a new classification of neurodegenerative disease. This article discusses: (i) the nature and degree of the overlap between different neurodegenerative disorders and includes a discussion of Alzheimer's disease, dementia with Lewy bodies, the fronto-temporal dementias, and prion disease; (ii) the factors that contribute to disease overlap, including historical factors, the presence of disease heterogeneity, age-related changes, the problem of apolipoprotein genotype, and the co-occurrence of common diseases; and (iii) whether the current nosological status of disorders should be reconsidered.