Medical researchers have used structural and functional imaging techniques to study various neurological phenomena. Humans are typically conscious for both structural and functional neuroimaging studies. The use of functional neuro-imaging techniques in mouse-based animal models is typically accomplished with restrained or anesthetized mice. A system was developed to perform functional imaging with single-photon emission computed tomography of awake mice to avoid the confounding influences of anesthesia or physical restraint. This review article provides an overview of the technique and how it is presently being used. The system is designed for brain imaging and uses infrared reflectors to track the head position as a function of time. The detected photons are acquired in list mode and are time-stamped. The position of the rotating gamma camera is also recorded as a function of time. These three sets of data are integrated together in an iterative image reconstruction program that performs motion compensation. The successful performance of the system is demonstrated in moving phantom and awake animal studies. The system and methodology has the potential of being a powerful tool in behavioral neuroimaging studies involving awake, unrestrained mice.