This chapter presents a state of the art summary of Von Hippel–Lindau Syndrome (VHL syndrome) relation to its biology, epidemiology, disease mechanisms, clinical signs, diagnosis, treatment and prognosis. An early description of VHL syndrome stems from the reports by Collins in 1894 and von Hippel in 1904 concerning the cases of familial retinal hemangioblastomas. VHL syndrome has an estimated incidence of 1 case per 36,000 live births, with first manifestations emerging in the second decade of life and complete penetrance by 70 years of age. The prototypic lesion of VHL syndrome is a central nervous system hemangioblastoma, which occurs in up to 72% of patients and often appears as a distinct, red, vascular mass with a thin layer of capsule in the cerebellum, brainstem, spinal cord, cauda equine, or supratentorial location. Diagnosis of VHL syndrome is based on clinical diagnostic criteria and molecular identification of a heterozygous germline VHL pathogenic variant.