Cerebral small vessel disease (SVD) is a leading cause of stroke and vascular dementia. The majority of cases are sporadic, occurring in the elderly hypertensive population. However, there also exist patients with familial disease. The most common form is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene. In recent years, other genes have also been found to cause familial SVD, such as COL4A1/A2, HTRA1, FOXC1 and TREX1. Genome wide association studies (GWAS) have also revealed loci associated with sporadic SVD strokes and its related features. This thesis explores the genetic basis of SVD primarily from the angle of the ‘one gene, one disease’ hypothesis. We explore the phenotype of familial SVD using CADASIL as a prototype. We next adopt a candidate gene approach to rare variant discovery using high throughput sequencing (HTS) techniques in two forms: 1) a multi-gene sequencing panel to examine the presence of rare variants in a cohort of 993 presumed-sporadic, early-onset SVD stroke patients, and 2) whole genome sequencing in 118 pedigrees with suspected familial SVD. We also evaluate the prevalence of known disease-causing mutations in the general population using a cohort of whole genome sequenced non-SVD patients, and other control databases. We demonstrate that a few presumed-sporadic SVD stroke patients may in fact have familial disease that was not previously diagnosed. We show that known and novel rare variants in candidate genes are found in our cohort of familial SVD patients, and suggest a possible role for rare variants in genes associated with related phenotypes and sporadic disease in this cohort. Finally, we identify known disease-causing variants in relatively high frequencies in the population, and show that conclusions on the pathogenicity of variants based on allele frequency and functional analyses may sometimes be misguided, thus highlighting the current limitations we face in the clinical interpretation of variants identified on HTS. In recent years genetic studies have revealed that pathways in different familial diseases are likely to converge in the pathogenesis of sporadic disease. Further uncovering the genetic basis of undiagnosed cases of familial SVD may shed light on the mechanisms underlying the sporadic form of disease, and may in turn drive the identification of potential therapeutic targets.