The COVID-19 pandemic is one of those global challenges that transcends territorial, political, ideological, religious, cultural, and certainly academic boundaries. Public health and healthcare workers are at the frontline, working to contain and to mitigate the spread of this disease. Although intervening biological and immunological responses against viral infection may seem far from the physical sciences and engineering that typically work with inanimate objects, there actually is much that can—and should—be done to help in this global crisis. In this Perspective, we convert the basics of infectious respiratory diseases and viruses into physical sciences and engineering intuitions, and through this exercise, we present examples of questions, hypotheses, and research needs identified based on clinicians’ experiences. We hope researchers in the physical sciences and engineering will proactively study these challenges, develop new hypotheses, define new research areas, and work with biological researchers, healthcare, and public health professionals to create user-centered solutions and to inform the general public, so that we can better address the many challenges associated with the transmission and spread of infectious respiratory diseases.