Starting with a forward genetic screen in the zebrafish, we have uncovered how dysregulated TNF expression causes necrosis of infected macrophages during tuberculous infection. The detailed dissection of the pathway has enabled us to identify readily available inexpensive drugs to intercept this pathogenic circuit. Through genetic studies on human TB cohorts, we have shown that the pathway we discovered in the zebrafish is relevant to humans, strongly impacting survival. Moreover our work has provided an ideal example of pharmacogenomics where individuals with specific genotypes are benefitted by specific host-targeting drugs. I will present this work that reveals new biology and identifies completely new classes of drugs for TB.