Cholesterol is an important metabolite and membrane component and is enriched in the brain owing to its role in neuronal maturation and function. In the adult brain, cholesterol is produced locally, predominantly by astrocytes. When cholesterol has been used, recycled and catabolized, the derivatives are excreted across the blood–brain barrier. Abnormalities in any of these steps can lead to neurological dysfunction. Here, we examine how precise interactions between cholesterol production and its use and catabolism in neurons ensures cholesterol homeostasis to support brain function. As an example of a neurological disease associated with cholesterol dyshomeostasis, we summarize evidence from animal models of Huntington disease (HD), which demonstrate a marked reduction in cholesterol biosynthesis with clinically relevant consequences for synaptic activity and cognition. In addition, we examine the relationship between cholesterol loss in the brain and cognitive decline in ageing. We then present emerging therapeutic strategies to restore cholesterol homeostasis, focusing on evidence from HD mouse models. Cholesterol has diverse roles in the brain, and precise regulation of cholesterol production and catabolism is essential for healthy brain function. This Review summarizes cholesterol regulation and function in the brain and discusses evidence of cholesterol dyshomeostasis in age-related neuropathology and a number of neurological diseases. In particular, the authors focus on Huntington disease and insights from rodent models. Key points: Cholesterol homeostasis in the brain is essential for healthy neuronal physiology, and dyshomeostasis of the cholesterol pathway has been implicated in neurological diseases and age-related neuropathology. Reduced cholesterol biosynthesis and levels are found in the brain of animal models of neurological diseases, including Huntington's disease (HD), as well as in aged animals. Strategies that increase cholesterol biosynthesis and/or levels in the brain, including adeno-associated viral delivery of genes involved in cholesterol homeostasis or direct delivery of exogenous cholesterol, restore neuronal physiology, cognitive decline and healthy behaviour in animal models of HD and ageing. [ABSTRACT FROM AUTHOR]