The manifestation of HIV-1-associated minor motor deficits or HIV-1-associated dementia indicates viral activity within the CNS. Highly active antiretroviral therapy (HAART) has a prophylactic effect, which does not protect all patients, because different pathomechanisms are involved. A CNS-specific therapeutic efficacy can be demonstrated for nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs; NNRTIs). To be effective in the CNS, HAART should contain either zidovudine or stavudine and NNRTI should be added if there is dinical or preclinical evidence of CNS involvement. Protease inhibitors may be sufficient to lower high systemic viral burden and thus protect the CNS from HIV-1 invasion.