This review focuses on issues pertinent to the epidemiology and clinical interpretation of resistance to nucleos(t)ide reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitor resistance mutations, and especially thymidine analog mutations, remain the most common form of resistance detected in drug-naive patients. At the same time, improved treatment strategies, changes in prescribing policies, and prompt management of treatment failure are changing the prevalence and patterns of nucleoside reverse transcriptase inhibitor resistance in treatment-experienced patients. The clinical interpretation of nucleoside reverse transcriptase inhibitor resistance is being increasingly refined, helped by improved understanding of resistance pathways, development of sophisticated methods of analysis of genotypic resistance patterns, and introduction of clinically relevant cutoffs. Correlation of genotypic and phenotypic resistance data to clinical outcomes is essential to allow appropriate interpretation. In some cases, phenotypic data, either obtained directly by phenotypic tests or extrapolated from genotypic results, provide the most immediate predictors of virologic response. In other cases, genotypic analyses identify mutations that impact on responses without showing a marked effect on the phenotype, by either acting as "sentinel" markers for the presence of resistance undetectable by standard methods, or by lowering the genetic barrier to the evolution of resistance. The potential benefits of nucleoside reverse transcriptase inhibitor resistance, through hypersusceptibility and fitness effects, are also increasingly understood and exploited in clinical practice. Although progress has been significant, there remain many challenges. It is often questioned whether genotypic scores and clinical cutoffs obtained by various methods and from frequently small datasets can be reliably extrapolated to the general population of treated patients. At the same time, there is a need to define the role of reverse transcriptase mutations that are identified by statistical analyses as being associated with nucleoside reverse transcriptase inhibitor exposure, but have unknown effects on virus phenotype and clinical outcome. Novel mechanisms have also been proposed to play a role in nucleoside reverse transcriptase inhibitor resistance, including changes in RNaseH that are not targeted by routine testing at present. One additional, currently unresolved issue is the clinical relevance of minority resistant species and the feasibility of introducing ultra-sensitive resistance tests in routine diagnostic settings. The most appropriate viral-load cutoff for performing resistance tests and the reliability of results obtained at low copy numbers are similarly controversial. In spite of these limitations, resistance testing with appropriate interpretation provides an important guide to successful treatment outcomes and necessary support to the introduction of new treatment strategies.