Recent advances in materials chemistry and composite materials design establish the foundations for classes of electronics with physical form factors that bridge the gap between soft biological organisms and rigid microsystems technologies. Skin-interfaced platforms of this type have broad utility in continuous clinical-grade monitoring of physiological status, with the potential to significantly lower the cost and increase the efficacy of modern health care. Development of materials and device designs for power supply systems in this context is critically important, and it represents a rapidly expanding focus of research in the chemical sciences. Reformulating conventional technologies into biocompatible platforms and co-integrating them into skin-interfaced systems demand innovative approaches in materials chemistry and engineering. In terms of physical properties, the resulting devices must offer levels of flexibility, stretchability, thickness, and mass density that approach those of the epidermis itself, while maintaining operational characteristics and mechanical durability for practical use outside of a laboratory or hospital. While nearly all commercially available components for energy storage and harvesting are rigid and planar, recent research provides options in devices that are biocompatible not only at the level of the constituent materials but also in terms of the mechanics and geometrical forms, with resulting capabilities for establishing stable, nonirritating, intimate interfaces to the skin for extended periods of time. This Account highlights the range of materials choices and associated device architectures for skin-interfaced power supply systems. The Account begins with an overview of the main design strategies, ranging from one-, two-, and three-dimensional engineered composite structures to active materials that are intrinsically stretchable. The following sections describe a broad collection of devices based on these concepts, starting with batteries and supercapacitors for storage and then photovoltaic, piezoelectric, triboelectric, and thermoelectric devices for harvesting. Representative examples highlight recent advances, with a focus on the relationship between the materials and the performance during deformation. A final section discusses the challenges and opportunities in this area. Continued efforts in fundamental chemical research will be critically important to progress in this emerging field of technology. For example, understanding the mechanisms by which physical deformations affect the intrinsic materials properties and the system-level performance requires further study. The development of stretchable and biocompatible solid electrolytes with high ionic conductivity is an example of a specific area of interest for energy storage devices. Here and in other storage and harvesting systems advanced materials are needed to provide robust barriers to environmental factors. Work to address these and other interesting challenges will demand multidisciplinary collaborations between chemists, materials scientists, bioengineers, and clinicians, all oriented toward establishing the foundations for technologies that could help to address global grand challenges in human health care.