This article focuses on the different types of transporter proteins that have been implicated in the influx and efflux of nucleoside-derived drugs currently used in the treatment of cancer, viral infections (i.e., AIDS) and other conditions, including autoimmune and inflammatory diseases. Genetic variations in nucleoside-derived drug transporter proteins encoded by the gene families SLC15, SLC22, SLC28, SLC29, ABCB, ABCC and ABCG will be specifically considered. Variants known to affect biological function are summarized, with a particular emphasis on those for which clinical correlations have already been established. Given that relatively little is known regarding the genetic variability of the players involved in determining nucleoside-derived drug bioavailability, it is anticipated that major challenges will be faced in this area of research.