This chapter focuses on CNS pathology directly causing sleepiness, as opposed to pathology that causes sleep disorders that result in sleepiness. Focal lesions cause sleepiness by directly involving one (or more) of the neuroanatomic regions subserving sleep or wakefulness. Paraneoplastic disorders such as anti-Ma2 encephalitis are also associated with sleepiness. Ma-2 is an onconeuronal protein linked with testicular and lung cancer. Methylphenidate, amphetamines, and modafinil are effective in the treatment of sleepiness in children with brain tumors. Infectious processes of the CNS, both diffuse and focal, can result in excessive sleepiness. Antiretroviral drugs, efavirenz and nevirapine have been linked to sleep disruption and vivid dreams, and zidovudine causes insomnia. The neuroanatomy of sleep and wakefulness is a complex interplay between numerous wake- and sleep-promoting centers and circadian factors. Hypothalamic damage, whether from neoplasm, stroke, multiple sclerosis (MS) plaque or neurocysticercosis, can result in the same secondary narcolepsy phenotype.