Radionuclide cardiac imaging has potential to assess underlying molecular, electrophysiologic, and pathophysiologic processes of cardiac disease. An area of current interest is cardiac autonomic innervation imaging with a radiotracer such as (123)I-meta-iodobenzylguanidine ((123)I-mIBG), a norepinephrine analogue. Cardiac (123)I-mIBG uptake can be assessed by planar and SPECT techniques, involving determination of global uptake by a heart-to-mediastinal ratio, tracer washout between early and delayed images, and focal defects on tomographic images. Cardiac (123)I-mIBG findings have consistently been shown to correlate strongly with heart failure severity, pre-disposition to cardiac arrhythmias, and poor prognosis independent of conventional clinical, laboratory, and image parameters. (123)I-mIBG imaging promises to help monitor a patient's clinical course and response to therapy, showing potential to help select patients for an ICD and other advanced therapies better than current methods. Autonomic imaging also appears to help diagnose ischemic heart disease and identify higher risk, as well as risk-stratify patients with diabetes. Although more investigations in larger populations are needed to strengthen prior findings and influence modifications of clinical guidelines, cardiac (123)I-mIBG imaging shows promise as an emerging technique for recognizing and following potentially life-threatening conditions, as well as improving our understanding of the pathophysiology of various diseases.