The nucleoside analogue reverse transcriptase inhibitor (RTI) emtricitabine and the nucleotide analogue RTI tenofovir disoproxil fumarate (tenofovir DF) have each shown antiviral activity against a number of HIV clinical isolates and cell lines. HIV variants with reduced susceptibility to emtricitabine and tenofovir have been selected for in vitro and have also been isolated from patients receiving the agents. Low rates of these variants have been observed in patients experiencing virological failure in large studies of emtricitabine- or tenofovir DF-containing therapy. Co-formulated oral emtricitabine/tenofovir DF was bioequivalent to the two agents as separate formulations in a pharmacokinetic trial in healthy volunteers. There are no published data on the clinical antiviral efficacy of co-formulated oral emtricitabine/tenofovir DF. However, each agent is effective in combination regimens with other drugs. Ongoing studies in antiretroviral-naive patients are evaluating the efficacy of the individual formulations given together in combination with efavirenz or lopinavir/ritonavir. In the latter trial, HIV RNA levels were reduced and CD4+ cell counts were increased at 24 and 48 weeks. Emtricitabine and tenofovir DF are generally well tolerated. Diarrhoea, nausea and vomiting were the most common adverse events reported with coadministered emtricitabine and tenofovir DF as separate formulations as part of combination therapy.