Breath sensors can revolutionize medical diagnostics by on-demand detection and monitoring of health parameters in a noninvasive and personalized fashion. Despite extensive research for more than two decades, however, only a few breath sensors have been translated into clinical practice. Actually, most never even left the scientific laboratories. Here, we describe key challenges that currently impede realization of breath sensors and highlight strategies to overcome them. Specifically, we start with breath marker selection (with emphasis on metabolic and inflammatory markers) and breath sampling. Next, the sensitivity, stability, and selectivity requirements for breath sensors are described. Concepts are elaborated to systematically address these requirements by material design (focusing on chemoresistive metal oxides), orthogonal arrays, and filters. Finally, aspects of portable device integration, user communication, and clinical applicability are discussed.