The sensation of pain is an aversive, sensory and emotional experience that is necessary to alert us to actual or potential tissue damage and is crucial to prevent injuries. This becomes evident by a group of orphan Mendelian genetic disorders of the peripheral sensory nervous system, which cause absent or reduced pain sensation. Affected individuals may sustain multiple self-inflicted injuries, repeated burns and trauma, disfiguring ulcerations and mutilations, which require frequent hospitalizations and cause lasting disability or even early fatality. Three higher-level pathologies with similar clinical consequences have been shown to underlie hereditary painlessness: Neurodevelopmental defects and altered excitability of sensory neurons, both subsumed under the term congenital insensitivity to pain (CIP), and sensory neurodegeneration, usually referred to as hereditary sensory and autonomic neuropathy (HSAN). CIP/HSAN can be transmitted as an autosomal recessive or autosomal dominant trait and has so far been linked to variants in 20 different disease-related genes. Known CIP/HSAN disease genes are involved in diverse molecular and cellular pathways, including neurotrophin signalling, function of voltage-gated ion channels or axonal transport. Other pathways related to known disease genes highlight the involvement of rather unexpected players such as sphingolipid metabolism, DNA and histone modifications, and membrane dynamics. Largely related to the genetic subtype, disease severity and progression are variable and impairment of other sensory modalities, autonomic disturbances or intellectual disability contribute to the patients’ clinical presentation. All forms of CIP/HSAN are rare, with a collective prevalence estimate of about 1.5-3:100,000.