Methods for identifying and understanding brain structure–function relations have evolved over the past century, from astute observations of selective impairments associated with focal brain damage to dissociations measured by combining quantitative neuropsychologic assessment and brain imaging. Enhanced spatial and temporal resolution in brain imaging modalities has led to refined visualization and quantification of the brain’s substructures, microstructural integrity, and functional connectivity of neural networks. The double dissociation model has been a gold standard used to demonstrate that a particular cognitive, emotional, sensory, or motor process is selectively related to a particular brain region or neural network and not to others. This model has provided a fruitful means for testing hypotheses of functional localization and enabled examination and establishment of component processes contributing to complex cognitive and motor functions, parsing multifactorial behaviors and identifying brain regions, and networks subserving these complex abilities. In this chapter we discuss the evolution of the dissociation model and highlight how the modifications of this model are used presently to establish selective brain–behavior relationships in disorders such as chronic alcoholism with a neuropathologic signature but no localizable, space-occupying lesion.