This chapter explores whether the disease process originates in the cerebellum or a cerebellar motor loop system, or in the brainstem. The majority of neuroimaging evidence is in favor of a central role of cerebellar involvement in the pathobiology of essential tremor (ET). ET has been hypothesized to be a neurodegenerative disease. Though many studies have found metabolic and structural changes that suggest loss of neuronal and/or fiber tract integrity in ET, there has been limited studies that have found no abnormalities among ET patients. Although the clinical features of ET and Parkinson's disease (PD) are distinctive, the presence of a range of different types of tremor in each disease remains a continued source of diagnostic difficulty for clinical neurologists. Recent evidence suggests that there might be an intermediate level of abnormality in the striatum in some ET cases, which is between that seen in healthy controls and PD cases.