Clinicians who care for patients infected with coronavirus disease 2019 (COVID-19) must wear a full suite of personal protective equipment, including an N95 mask or powered air purifying respirator, eye protection, a fluid-impermeable gown, and gloves. This combination of personal protective equipment may cause increased work of breathing, reduced field of vision, muffled speech, difficulty hearing, and heat stress. These effects are not caused by individual weakness; they are normal and expected reactions that any person will have when exposed to an unusual environment. The physiologic and psychologic challenges imposed by personal protective equipment may have multiple causes, but immediate countermeasures and long-term mitigation strategies can help to improve a clinician’s ability to provide care. Ultimately, a systematic approach to the design and integration of personal protective equipment is needed to improve the safety of patients and clinicians.