Improved tuberculosis (TB) diagnosis and treatment through the DOTS and Stop TB strategies have saved millions of lives; however, their impact on TB incidence has been disappointing and the scale of the epidemic remains overwhelming. To reduce the incidence of TB, the drivers of the epidemic and social determinants of TB need to be addressed. These include co-morbidities and substance use and, moreover, the social and economic conditions that determine both the course of the TB epidemic and exposure to these risk factors. Doing so builds on the history of TB prevention and treatment during the public health revolution that resulted in a dramatic reduction in incidence in many countries. Addressing the social determinants is also imperative to address pervasive inequities in the incidence, mortality and morbidity of TB between different population groups, including in the performance of health systems in delivering diagnostic and treatment interventions, and in the financial consequences of people seeking care. Action on the social determinants can be categorised in terms of health-sector interventions, intersectoral policies impacting across society, and measurement and research to better understand inequities and links between TB and other factors. TB programmes cannot carry out these actions alone; however, they can make important contributions in the delivery of interventions and in advocating and negotiating for intersectoral efforts. The considerable progress seen in the clinical care of TB needs to be sustained; however, the attainment of TB targets, including elimination by 2050, will require expansion of the lens of TB control efforts beyond ‘business as usual’ to address the social determinants of the disease.