Developing drugs to combat tuberculosis (TB), can be frustrating business. A gene essential to the bacteria’s lifecycle is discovered, scientists rush to develop drugs that inhibit the target, and then—disappointment. Volleys of compounds hurled at the essential gene target have little impact on microbial growth. The bacteria live on. The scientists return to the drawing board. Now, a new study in Cell helps explain why target-based antibiotics have had so much trouble getting off the ground. One answer is that essential gene targets differ in their degree of vulnerability to antibiotics. An ideal target, the researchers found, is so vulnerable to attack that the cell cannot survive when it is even slightly inhibited. Invulnerable genes, on the other hand, can weather nearly total inhibition, eking out just enough target activity to keep the cell alive while beset with antibiotics. Further, the authors quantified vulnerability in a pathogen for the first time, producing an index that ranks almost every essential gene in Mycobacterium tuberculosis by the amount of inhibition necessary to disable the gene and cripple the cell.