Despite the identification of Mycobacterium tuberculosis as the cause of tuberculosis (TB) more than a century ago, diagnosing TB in resource-poor countries remains a challenge, especially in people living with HIV. In the past decade, important research investments have been made towards the development of new diagnostics for TB and the Xpert(®) MTB/RIF assay (Cepheid, CA, USA) has emerged as one of the most promising. In this article, we review the current knowledge on Xpert MTB/RIF, discuss the potential value of Xpert MTB/RIF as a point-of-care diagnostic for drug-sensitive and drug-resistant TB, and outline the potential indications for the assay in resource-limited, high-HIV burden settings. We also discuss key research questions that need to be addressed prior to possible large-scale implementation of the assay.