Since their advent the nucleoside and nucleotide reverse transcriptase inhibitors have consolidated their position as the 'backbone' of many antiretroviral therapy regimens. The ability of this class of drugs to combine successfully with members of their own as well as other antiretroviral classes has enabled the effective suppression of HIV replication to occur. Many of these therapeutic combinations rely on synergistic interactions to achieve this. There are, however, also many unfavourable pharmacokinetic and pharmacodynamic interactions between the members of nucleoside/nucleotide reverse transcriptase inhibitors, as well as with other antiretroviral classes and non-HIV drugs. This article aims to identify clinically relevant, beneficial and detrimental interactions of this class of antiretroviral agent.