Nucleoside and nucleotide analogues are essential for the design of effective antiretroviral regimens. There are currently many options for the selection of such drug backbones, although not all combinations will display optimal results. The concomitant administration of certain drugs should be avoided due to high rates of toxicity (ddl/d4T, ddl/TDF), antagonism (AZT/d4T, 3TC/FTC) and/or a greater risk of virological failure (ddl/TDF, ABC/TDF). The understanding of the plasmatic and intracellular metabolism of nucleoside/nucleotide analogues is crucial for deciding the optimal posology of each drug and the better dual combinations to be selected. Interferences between the pathways involved into the intracellular activation of some nucleoside/nucleotide analogues may help to understand why certain drug combinations should be avoided.