Modern neuroimaging techniques are providing revolutionary insights into the human brain connectome. We are now able to study—in living people—large-scale brain networks predicted from non-human primate tract tracing investigations and lesion neuropsychology. I will review knowledge of the localization and function of brain networks in the healthy brain, and evidence that measures of these networks illuminate individual differences in cognition, affect, and sensorimotor function. The modulation of network connectivity in relation to task performance, pharmacologic manipulation, or brain stimulation is providing new insights into neuroplasticity. Age-related cognitive decline may be explained in part by a “compromised connectome”; older adults lucky enough to be “superagers”—with youthful cognitive function—have preserved anatomy in key nodes of large-scale cognitive-affective brain networks. Patients with neurodegenerative diseases develop disconnection, dysfunction, and atrophy within brain networks subserving cognitive, affective, and sensorimotor function related to symptoms of their illness. Neurodegenerative diseases appear to progress in part by following the pathways of the brain’s connectome. As a result of attending this lecture, the participant will increase their knowledge of 1) healthy human brain networks subserving normal brain function, and 2) impaired network connectomics in aging and neurodegenerative disease.