Primary mitochondrial disorders (PMD) are a heterogenous group of genetic diseases that can cause multiorgan dysfunction resulting from impaired energy production and oxidative stress (Muraresku CC et al., Curr Genet Med Rep 6(2):62–72, 2018. https://doi.org/10.1007/s40142-018-0138-9 ). Nearly 400 genes in the nuclear (nDNA) and mitochondrial (mtDNA) genomes that encode proteins associated with all facets of mitochondrial function have been implicated to cause PMD (Gorman GS et al., Nat Rev Dis Primers 2:16080, 2016. https://doi.org/10.1038/nrdp.2016.80 ). Symptomology associated with PMD may manifest as isolated organ or multisystemic involvement with onset spanning from infancy to adulthood. The high prevalence of neuropsychiatric and neuropsychological disorders in PMD has been documented in the literature yet remains underdiagnosed and undertreated (Fattal O et al., Psychosomatics 47(1):1–7, 2006. https://doi.org/10.1176/appi.psy.47.1.1 ). The two cases presented here demonstrate the diverse neuropsychological and neuropsychiatric pathology that may develop from underlying multifactorial defects in the central nervous system and the management challenges that clinicians face while caring for these patients.