Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are among the earliest developed functional imaging techniques. SPECT images are acquired after administration of a radioactive compound that emits single photons that can be detected by gamma-cameras. Similar to SPECT, PET imaging also uses radioactive biotracers to monitor physiological processes. However, better localization is achieved in PET imaging. Functional magnetic resonance imaging (fMRI) can be used with several different experimental designs to answer distinct questions about brain function. Multiple sclerosis (MS) disease-related brain changes including the presence of focal lesions and atrophy can complicate functional neuroimaging studies. Functional imaging is utilized to study fatigue, depression, motor system, vision, cognition, and for interpretation of cortical reorganization. Functional imaging plays a much larger role in clinical trials for MS involving remyelination, cell grats, neuroprotective treatments, and in illuminating the mechanisms of progressive disease.