Protocols have a well-established role in clinical research and are increasingly being used to direct routine clinical care. In this article, we review the differing goals of research and clinical protocols and outline the similar process for their development. We use the mechanical ventilation protocol of the ARDS Network trial comparing small with traditional tidal volumes as an example. As a starting point for debate, we also suggest guiding principles and specific components of a protocol for high-frequency oscillatory ventilation.