Autopsy remains the gold standard for diagnosis of neurodegenerative disease. Neurodegeneration is defined as the progressive loss of selectively vulnerable neurons in specific anatomic networks, thus leading to neuronal death and cognitive impairment. Neurodegenerative diseases are therefore characterized by the clinical phenotype (e.g. a dementia syndrome), anatomic patterns of atrophy or vulnerability, and pathology at cellular and molecular levels. Is there concordance between clinical manifestations of disease and the underlying pathology that causes symptoms? If so, what are the anatomic targets and molecular fingerprints of specific neurodegenerative diseases? The evaluation of postmortem pathology underlying dementia is thus critical for understanding the substrates of disease, developing disease-specific biomarkers, and retrospectively identifying antemortem clinical features reliable for early diagnosis. A major challenge that impedes these developments, however, is the heterogeneity of pathologies underlying dementia syndromes and old age. This lecture will review the scientific literature on clinicopathologic relationships in focal dementia syndromes like dementia of the Alzheimer’s type, Primary Progressive Aphasia (PPA), and behavioral variant Frontotemporal Dementia (bvFTD). It will also introduce participants to underlying pathologic features of unique elderly individuals, known as “SuperAgers”, who appear to resist neurodegeneration. The overarching theme is that the relationship between cognitive phenotype during life and underlying pathology at death is not absolute but probabilistic. In the clinic and in the laboratory, the neuropsychologist can benefit from a nuanced view of the postmortem factors that contribute to vulnerability versus resistance in the field of neurodegeneration.