Drug-resistant tuberculosis (DRTB) is a global health problem with about half a million people worldwide contracting a resistant germ each year. Effective care of the affected individual and eradication of tuberculosis are both dependent on its early and accurate detection. This chapter reviews the modern diagnostic approach to DRTB. It describes the early indicators of lack of response to anti-tubercular treatment that should raise an initial suspicion of DRTB; the possible causes of lack of improvement; the choice between the available methods and their application to drug sensitivity testing (DST); and the interpretation of the results of nucleic acid amplification tests, especially when they are not concordant with other lab tests. It also explores the lab- and pathogen-related factors that might impact the interpretation of DST, and discusses the drugs to which cross-resistance should be anticipated.