Cardiac sympathetic activity plays a key role in supporting cardiac function in both health and disease conditions, and nuclear cardiac imaging has always represented the only way for the non-invasive evaluation of the functional integrity of cardiac sympathetic terminals, mainly through the use of radiopharmaceuticals that are analogues of norepinephrine and, in particular, with the use of 123I-mIBG imaging. This technique demonstrates the presence of cardiac sympathetic dysfunction in different cardiac pathologies, linking the severity of sympathetic nervous system impairment to adverse patient’s prognosis. This article will outline the state-of-the-art of cardiac 123I-mIBG imaging and define the value and clinical applications in the different fields of cardiovascular diseases.