Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages. Phage therapy has undergone a revitalization in the last 7 years, and a growing number of clinical trials are underway. This review provides a comprehensive view on the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions.