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Cobicistat and ritonavir are structurally distinct compounds that both potently inhibit cytochrome P450 (CYP) 3A, the metabolizing enzyme primarily responsible for the elimination of several antiretroviral medications, and, as such, are pharmacokinetic boosters for antiretroviral agents that require longer dosing intervals. Recently, cobicistat was approved for the treatment of HIV-1 infection in treatment-naive adults as a component of a single-tablet regimen consisting of cobicistat-boosted elvitegravir plus emtricitabine and tenofovir disoproxil fumarate. While studies have demonstrated that boosting with either cobicistat or ritonavir results in comparable plasma exposure of the target antiretroviral agent, a better understanding of drug-drug interactions between cobicistat- and ritonavir-boosted antiretrovirals and other medications will inform treatment decisions in HIV-infected patients. In connection with their distinct structural properties, COBI and RTV differ with respect to their drug-drug interaction profiles. Compared with ritonavir, cobicistat lacks induction potential and is a more specific inhibitor of 3A and therefore, has reduced effects on other CYP isoforms. To date, more studies have assessed ritonavir drug-drug interactions with other medications than have assessed cobicistat drug-drug interactions. The objective of this article is to review the drug-drug interactions when cobicistat- or ritonavir-boosted elvitegravir, cobicistat, or elvitegravir/cobicistat/emtricitabine/tenofovir are coadministered with antiretroviral therapies or drugs that are either substrates, inducers, or inhibitors of the CYP3A metabolic pathway, as well as with drugs that alter intra-gastric pH or are substrates of P-gp, in order to inform the proper use of elvitegravir/cobicistat/emtricitabine/tenofovir.