A TB diagnostics scale-up effort in sub-Saharan Africa is expanding targeted next-generation sequencing (tNGS) after an Eswatini pilot demonstrated high clinical impact. Researchers reported that tNGS testing directly from sputum led to treatment changes for more than half of patients tested over a 3.5-year period, with nearly 90% treatment success. The program, Sub-Saharan SeqNET, is supported by €2.3 million of funding and draws on findings about diagnostic-escape TB strains—cases that evaded common assays including Cepheid’s Xpert MTB/RIF due to specific mutations. Eswatini’s Ministry of Health and partners including Baylor College of Medicine and Leibniz Association collaborators drove the implementation. With the WHO endorsing tNGS for drug resistance testing, the initiative’s next phase focuses on regional rollout and operationalizing a sequencing-first diagnostic pathway.