Cerebral small vessel disease (SVD) is a vascular disorder that increases the risk of stroke and dementia and is diagnosed through brain MRI. Current primary prevention and secondary treatment of SVD are focused on lifestyle interventions and vascular risk factor control, including blood pressure reduction. However, these interventions have limited effects, a proportion of individuals with sporadic SVD do not have hypertension, and SVD shows strong familial and genetic underpinnings. Here, we describe the increasing evidence that cerebral endothelial cell dysfunction is a key mechanism of SVD. Dysfunctional endothelial cells can cause cerebral blood vessel dysfunction, alter blood-brain barrier integrity and interfere with cell-cell interactions in the neuro-glial-vascular unit, thereby causing damage to adjacent brain tissue. Endothelial cells in SVD may become dysfunctional through intrinsic mechanisms via genetic vulnerability to SVD and/or via extrinsic factors such as hypertension, smoking and diabetes. Drugs that act on endothelial pathways are already looking promising in clinical trials, and understanding their action on endothelial cells and the surrounding brain may lead to the development of other therapies to limit disease progression and improve outcomes for individuals with SVD.