The global fight against tuberculosis (TB) has gained momentum since the adoption of the ‘End TB Strategy’ in 2014 [1], and the inclusion of ‘ending the TB epidemic’ as a target within the Sustainable Development Goals (SDGs) 3 in 2015 [1,2]. During the past two decades, improvements in quality-assured diagnosis and treatment of TB has contributed to saving more than 40 million lives and reducing TB mortality rates by more than 40% globally [3]. However, we have not been as successful in reducing TB incidence rates: TB incidence is declining by 2% per year globally, far behind the pace necessary to meet the End TB targets [1,3]. Therefore, adopting a holistic approach that combines interventions that are biomedically oriented or focused on social protection, and that are tailored to regional, national and local contexts, is required. As such, countries will need to strengthen their health and social sectors (e.g., by making progress towards achieving universal health coverage, or increasing social protection), as emphasized within the framework of the new SDG agenda [2]. Yet, all this may still not be enough to end the TB epidemic, and will further require not just innovation of novel tools, but also innovative ways of using existing tools, that is shaped by emerging evidence from the field. This Special Issue provides an opportunity to publish the compelling evidence right from the field level in regard to the essentials of operationalizing the principles, pillars and components of the End TB Strategy and the United Nations High-Level Meeting (UNHLM) on TB.