Tuberculosis (TB) claims a life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy. But why have we not progressed towards the eradication of the disease? There is no simple answer, although apathy, politics, poverty and our inability to fight the chronic infection have all contributed. Drug resistance and HIV-1 are also greatly influencing the current TB battle plans, as our understanding of their complicity grows. In this Review, recent efforts to fight TB will be described, specifically focusing on how drug discovery could combat the resistance and persistence that make TB worthy of the moniker 'The Great White Plague'.