Patients with Parkinson's disease present with signs and symptoms of dysregulation of the peripheral autonomic nervous system that can even precede motor deficits. This dysregulation might reflect early pathology and therefore could be targeted for the development of prodromal or diagnostic biomarkers. Only a few objective clinical tests assess disease progression and are used to evaluate the entire spectrum of autonomic dysregulation in patients with Parkinson's disease. However, results from epidemiological studies and findings from new animal models suggest that the dysfunctional autonomic nervous system is a probable route by which Parkinson's disease pathology can spread both to and from the CNS. The autonomic innervation of the gut, heart, and skin is affected by α-synuclein pathology in the early stages of the disease and might initiate α-synuclein spread via the autonomic connectome to the CNS. The development of easy-to-use and reliable clinical tests of autonomic nervous system function seems crucial for early diagnosis, and for developing strategies to stop or prevent neurodegeneration in Parkinson's disease.