In this review we critically assess biomarkers of the direct effects of HIV related brain disease. This area is becoming increasingly complex because of the presence of confounds and varying degrees of activity of HIV brain disease. Sensitive and specific biomarkers are urgently needed although existing biomarkers do have some utility. The review will focus on the practical implications of the more established biomarkers. We discuss blood, cerebrospinal fluid and neurophysiological biomarkers but not neuroimaging techniques as they are beyond the scope of this review.