Neuroimaging methods such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) provide a unique opportunity to explore activity across the entire human brain in many different behaviors. An important additional feature is the ability to examine interacting neural systems using methods that focus on the covariances of activity. Two of these methods, partial least squares and structural equation modeling, are presented with specific examples. Shifting prefrontal and limbic interactions were observed in a working memory task for faces. In an episodic memory retrieval study, the activity of right prefrontal cortex was related to either memory search or successful retrieval depending on its interactions with other brain regions. This latter observation implies that regional activity must be evaluated within the neural context in which it occurs. The general hypothesis that learning and memory are emergent properties of network interactions is discussed, emphasizing that a region can play a different role across many functions and that role is governed by its interactions with anatomically related regions.