Mitochondrial disorders, in particular respiratory chain diseases (RCDs), present either as single organ problem or as multi-system disease. One of the most frequently affected organs in RCDs, in addition to the skeletal muscle, is the central nervous system (CNS). CNS manifestations of RCDs include epilepsy, stroke-like episodes, migraine-like headache, ataxia, spasticity, movement disorders, psychosis, demyelination, calcification, but also dementia. Cognitive impairment may be a feature of syndromic as well as non-syndromic RCDs. Syndromic RCDs associated with cognitive impairment include MELAS, KSS, Leigh syndrome, and many others. RCDs with cognitive decline not only result from mtDNA mutations but also from mutations in nuclear genes. At onset there is often no general intellectual deterioration in these patients but specific cognitive deficits, particularly in the visual construction, attention, abstraction, or flexibility. Diagnosis of cognitive impairment from RCDs is based on neuropsychological testing, imaging studies, including MRI, PET, SPECT, or MR-spectroscopy, CSF investigations, or electroencephalography. Therapeutic strategies for dementia in RCDs rely on symptomatic measures. Only single patients may profit from cholinesterase inhibitors or memantine, antioxidants, vitamins, or other substitutes. Overall, cognitive decline in RCDs (mitochondrial dementia) needs to be included in the differentials of dementia.