From the onset of the HIV/AIDS epidemic, the use of licit and illicit drugs has been investigated for its potential impact on HIV disease progression. Findings from a large number of laboratory-based studies indicate that drug abuse may exacerbate HIV disease progression; however, epidemiological studies have shown mixed results. This article presents a review of findings from both laboratory-based and epidemiologic investigations. In addition, we provide a careful evaluation of methodological strengths and limitations inherent to both study designs in order to provide a more nuanced understanding of how these findings may complement one another.