Magnetic resonance imaging (MRI) is very sensitive for the detection of white matter lesions (WML), which occur even in normal ageing. Intrinsic WML should be separated from physiological changes in the ageing brain, such as periventricular caps and bands, and from dilated Virchow-Robin spaces. Genuine WML are best seen with T2-weighted sequences such as long TR dual-echo spin-echo or FLAIR (fluid-attenuated inversion recovery); the latter has the advantage of easily separating WML from CSF-like lesions. Abnormal T2 signal in MRI is not specific, and can accompany any change in tissue composition. In the work-up of WML in small vessel disease, magnetic resonance angiography can be used to rule out (concomitant) large vessel disease, and diffusion-weighted MRI to identify new ischaemic lesions (amidst pre-existing old WML). The differential diagnosis of WML includes hereditary leukodystrophies and acquired disorders. The leukodystrophies that can present in adult age include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenomyeloneuropathy, mitochondrial disorders, vanishing white matter, and cerebrotendinous xanthomatosis. These metabolic disorders typically present with symmetrical abnormalities that can be very diffuse, often with involvement of brainstem and cerebellum. Only the mitochondrial disorders tend to be more asymmetric and frequently involve the grey matter preferentially. Among the acquired white matter disorders, hypoxic-ischaemic causes are by far the most prevalent and without further clinical clues there is no need to even consider the next most common disorder, i.e. multiple sclerosis (MS). Among the nonischaemic disorders, MS is far more common than vasculitis, infection, intoxication and trauma. While vasculitis can mimic small vessel disease, MS has distinctive features with preferential involvement of the subcortical U-fibres, the corpus callosum, temporal lobes and the brainstem/cerebellum. Spinal cord lesions are very common in MS, but do not occur in normal ageing nor in small vessel disease.