123I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with interest in many disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy can capture functional impairment and rarefaction of sympathetic terminals (which manifest as reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased sympathetic outflow (which can be visualized as high washout rate). These findings have been consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening arrhythmias over a follow-up of less than 2 years. Despite these promising findings, 123I MIBG scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk stratification, and has then never entered the stage of widespread adoption into current clinical practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction, genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several other conditions characterized by impaired sympathetic myocardial innervation. In the present chapter we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the current unresolved issues, and the possible directions of future research.