Substance abuse remains a major obstacle in treating HIV-infected patients. The high prevalence of drug use is responsible for lack of adherence and severe drug interactions to antiretroviral therapy in HIV positive individuals. Over the past decade, newer therapies for HIV have been developed by targeting different stages of HIV life cycle. Of importance, targeting initial binding with receptor and genome integration by CCR5 antagonists and integrase inhibitors, respectively have been effective in reducing viral loads in clinical trials. However, most of these recently approved or investigational antiretroviral drugs are also metabolized by cytochrome P450 (CYP) enzymes. Thus, substance abuse mediated changes in level of CYP enzymes (induction or inhibition) may result in severe drug interactions, failure of therapy, rapid progression to AIDS, and increased mortality in HIV patients who are treated with regimens containing CCR5 antagonists and integrase inhibitors. In this review, we have discussed the pharmacokinetic data, efficacy, lack of adherence to these therapies in drug abusers, and CYP-mediated potential drug interactions for CCR5 antagonists and integrase inhibitors in HIV-infected drug abusers.