Mutations in the NOTCH3 gene can lead to small vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other mutations in NOTCH3, including cysteine-sparing missense mutations, or frameshift and premature stop codons, can lead to small vessel disease phenotypes of variable severity or penetrance. There are currently no disease-modifying therapies for small vessel disease, including those associated with NOTCH3 mutations. A deeper understanding of underlying molecular mechanisms and clearly defined targets are needed to promote the development of therapies. This review discusses two key pathophysiological mechanisms believed to contribute to the emergence and progression of small vessel disease associated with NOTCH3 mutations: abnormal Notch3 aggregation and aberrant Notch3 signaling. This review offers a summary of the literature supporting and challenging the relevance of these mechanisms, together with an overview of available preclinical experiments derived from these mechanisms. Through the review, knowledge gaps and future research directions are highlighted. In view of recent evidence demonstrating the relatively high frequency of NOTCH3 mutations in the population, and their potential role in promoting small vessel disease, progress in the development of therapies for NOTCH3 -associated small vessel disease is urgently needed.