Building on several synthetic advances in recent years, Andrew G. Myers and coworkers at Harvard University have demonstrated that a novel pathway for making tetracycline compounds is broadly applicable for preparing diverse new antibiotics (J. Am. Chem. Soc., DOI: 10.1021/ja806629e). Tetracyclines, which consist of four linearly fused rings, designated A, B, C, and D, were discovered 60 years ago and quickly became an important class of broad-spectrum antibiotics. Because a practical synthetic route had never been developed, scientists previously relied on fermentation processes or on "semisynthetic" modification of natural products to make tetracyclines. That limitation, plus increasing bacterial resistance to the drugs, is pushing researchers to devise new strategies. In prior work, Myers' group developed a fully synthetic route to tetracyclines using a key cyclohexenone precursor that they developed, which contains the A and B rings, and a D-ring phenyl ester precursor. When these components couple, the C ring forms. Now, the team has greatly expanded the modular strategy by using diverse phenyl esters to make more than 50 tetracyclines and five-ring pentacycline analogs. The pentacycline shown exhibits the most potent antibiotic activity of the new compounds, with an efficacy in mouse studies similar to that of tetracycline.