Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) should be suspected in patients presenting with migraine, cerebral ischemic events, mood disturbances, apathy, and progressive cognitive impairment. Clinical suspicion is strengthened by a positive family history and/or the presence of one or more subcortical infarcts in deep white matter. The pathologic hallmark of CADASIL is the presence of deposits of granular osmiophilic material (GOM) in the small vessels of brain and other organs, and in skin where they can be identified by electron microscopy; however, it is not sufficiently sensitive, although highly specific. It is still debated if GOM deposits are part of CADASIL pathogenesis or only represent an epiphenomenon in this disease. Progressive degeneration of the smooth muscle layer surrounding small arterioles seems to be due to mutations in the NOTCH3 gene leading to an odd number of cysteine residues in the extracellular domain of the coded protein. Therefore, diagnosis of CADASIL is unequivocally confirmed by finding such specific stereotyped mutations in the NOTCH3 gene. Recently, however, noncanonical NOTCH3 mutations have been described in subjects with hereditary small-vessel disease of the brain but without GOM deposits and NOTCH3 accumulation. This has raised the debate on the existence of a different clinical phenotype called CADASIL-like syndrome. Several animal models expressing NOTCH3 mutations have been realized providing new opportunities to explore molecular and pathophysiological mechanisms of CADASIL and addressing the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. At present, there is no treatment of proven efficacy to stop or delay the progression of CADASIL; pharmacological support is specific for each single clinical manifestation of the disease. Rehabilitation, physiotherapy and psychological support are important in this severe chronic debilitating disease.