Genotypic resistance testing is now a standard of care in HIV management. Although there are clear, published guidelines to recommend the appropriate use of these tests, clinicians and scientists still struggle to determine the optimal use of resistance tests given the finite budgets and time constraints under which they work. In this article we discuss some 'real-life' clinical situations and aim to provide a useful insight into when and where genotypic resistance testing can be optimally applied in the management of HIV-positive adults.