Central or peripheral neurological disorders can manifest with autonomic failure or autonomic hyperactivity, which may affect the sympathetic, parasympathetic and/or enteric nervous systems. Disorders causing autonomic failure can be classified according to the presence or absence of associated neurological manifestations, such as peripheral neuropathy or parkinsonism, and their temporal profile (acute or subacute, chronic progressive, static, or episodic). A systematic approach allows focused evaluation to detect treatable, potentially disabling or life-threatening conditions. Subacute isolated autonomic failure affecting sympathetic, parasympathetic and enteric nervous system function, in various combinations, occurs in autoimmune autonomic ganglionopathy, which might be the first manifestation of an underlying neoplasm. Autonomic failure can be an important feature of several types of peripheral neuropathy, including sensorimotor peripheral neuropathies, sensory ganglionopathy, and distal painful peripheral neuropathies. Progressive autonomic failure occurs in neurodegenerative synucleinopathies such as multiple system atrophy and Lewy body disorders. Autonomic failure may also occur in hereditary leukoencephalopathies or prion disorders. This Review outlines the clinical approach to patients with generalized autonomic failure, focusing predominantly on classification and diagnosis, but also touching briefly on treatment and management.