In this Account, we detail recent progress in wearable bioelectronic devices and discuss the future challenges and prospects of on-body noninvasive bioelectronic systems. Bioelectronics is a fast-growing interdisciplinary research field that involves interfacing biomaterials with electronics, covering an array of biodevices, encompassing biofuel cells, biosensors, ingestibles, and implantables. In particular, enzyme-based bioelectronics, built on diverse biocatalytic reactions, offers distinct advantages and represents a centerpiece of wearable biodevices. Such wearable bioelectronic devices predominately rely on oxidoreductase enzymes and have already demonstrated considerable promise for on-body applications ranging from highly selective noninvasive biomarker monitoring to epidermal energy harvesting. These systems can thus greatly increase the analytical capability of wearable devices from the ubiquitous monitoring of mobility and vital signs, toward the noninvasive analysis of important chemical biomarkers. Wearable enzyme electrodes offer exciting opportunities to a variety of areas, spanning from healthcare, sport, to the environment or defense. These include real-time noninvasive detection of biomarkers in biofluids (such as sweat, saliva, interstitial fluid and tears), and the monitoring of environmental pollutants and security threats in the immediate surrounding of the wearer. Furthermore, the interface of enzymes with conducting flexible electrode materials can be exploited for developing biofuel cells, which rely on the bioelectrocatalytic oxidation of biological fuels, such as lactate or glucose, for energy harvesting applications. Crucial for such successful application of enzymatic bioelectronics is deep knowledge of enzyme electron-transfer kinetics, enzyme stability, and enzyme immobilization strategies. Such understanding is critical for establishing efficient electrical contacting between the redox enzymes and the conducting electrode supports, which is of fundamental interest for the development of robust and efficient bioelectronic platforms. Furthermore, stretchable and flexible bioelectronic platforms, with mechanical properties similar to those of biological tissues, are essential for handling the rigors of on-body operation. As such, special attention must be given to changes in the behavior of enzymes due to the uncontrolled conditions of on-body operation (including diverse outdoor activities and different biofluids), for maintaining the attractive performance that these bioelectronics devices display in controlled laboratory settings. Therefore, a focus of this Account is on interfacing biocatalytic layers onto wearable electronic devices for creating efficient and stable on-body electrochemical biosensors and biofuel cells. With proper attention to key challenges and by leveraging the advantages of biocatalysis, electrochemistry, and flexible electronics, wearable bioelectronic devices could have a tremendous impact on diverse biomedical, fitness, and defense fields.