This article reviews the four ways by which large-scale, neurobiologically realistic modeling can be used in conjunction with functional neuroimaging data, especially that obtained by functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), to help investigators understand the neural bases for sensorimotor and cognitive functions. The conceptually distinct purposes served are: (1) formulating and implementing specific hypotheses about how neuronal populations mediate a task, which will be illustrated using models of visual and auditory object processing; (2) determining how well an experimental design paradigm or analysis method works, which will be illustrated by examining event-related fMRI; (3) investigating the meaning in neural terms of macro-level concepts, which will be illustrated using functional connectivity; and (4) combining different types of macroscopic data with one another, which will be illustrated using transcranial magnetic stimulation (TMS) and PET.