While tobacco is a well-known risk factor for non-communicable diseases, the substantial burden of tobacco use on infectious diseases has been overlooked. In low- and middle-income countries, the concurrent tobacco, HIV, and TB epidemics amplify the potential devastation of each epidemic alone, and threatens HIV- and TB-related public health advances. Smoking is a cause of TB infection and disease progression and worsens treatment outcomes and survival in persons living with HIV. However, tobacco cessation has not yet been integrated into most TB and HIV treatment settings, and conventional tobacco cessation interventions face additional obstacles in these settings. This talk will describe the breadth of the syndemic, explore the impact of tobacco and tobacco cessation on TB- and HIV-related outcomes, and present novel cessation strategies for these at-risk populations in high burden, low-resource settings.