Antimicrobial resistance is threatening the management of infections such as pneumonia, tuberculosis, malaria, and AIDS. In the past, resistance could be handled by development of new drugs active against resistant microbes. However, the pharmaceutical industry has reduced its research efforts in infections; genomics has not delivered the anticipated novel therapeutics; new regulatory requirements have increased costs; antibiotic use in common infections—eg, bronchitis and sinusitis—is questioned; and, compared with other drugs, return on investments is lower for antimicrobials. To avoid a serious threat to public health, academia, biotechnology and pharmaceutical industry, regulators, and healthcare providers must find solutions to this problem. Academia should concentrate on technologies to unlock new drug targets, and industry on drug candidates. In addition, regulators and pharmaceutical companies should agree on new clinical-trial designs so that information on therapeutic efficacy is generated in fewer patients—eg, by studying pharmacodynamics of antimicrobials in patients with defined infections.