The prevalence of alcohol use among HIV-infected patients undergoing antiretroviral (ARV) treatments has raised several concerns related to key therapeutic indices. These include drug interactions, compliance, efficacy and toxicity with the possibility of accelerated disease progression. Interaction of ARVs with alcohol can result in therapeutic failures or place patients at significant risk for toxicities. Research findings in this particular area are, however, limited and sometimes conflicting. This review focuses on alcohol and ARV interactions affecting testicular and spermatogenic indices. Antiretroviral drugs are known to negatively impact testicular functions via altered mitochondrial DNA and oxidative stress mechanisms. Interaction with alcohol can significantly affect seminal fluid concentration of ARVs. Habitual consumption of alcohol causes testicular hypofunction with potential for lowered fertility. Concomitant use of ARVs appears to act synergistically to exacerbate this toxicity. Alcohol also induces cytochrome P450 (CYPs) microsomal enzymes, which in turn affect ARVs metabolized by these enzymes. In the presence of ARVs with strong inhibitory activity, increased bioavailability with toxicities predominates. In addition, alcohol and ARVs have pronounced effects on membrane-associated drug transporters. Alcohol alters the properties of the lipid bilayer by changing membrane permeability and protein distribution. Since drug transporters critical to pharmacokinetics are integral membrane proteins, alcohol tends to diminish the activity of both the efflux and influx transporters. While excessive alcohol precipitates accelerated hypogonadism, future research needs to be directed to quantifying these effects of alcohol and ARVs in human testicular tissue.