Recent advances in the development of in-body bioelectronic systems are providing new opportunities for the clinical management of various diseases and disorders. These emerging technologies are tailored to specific organs and are beginning to blend both diagnostic sensing and therapeutic actuation. The aim of these systems is to seamlessly integrate with the physiological environment, as illustrated by the diverse device strategies discussed throughout this article. Next generation modalities, such as optogenetics combining gene therapy with devices for photostimulation, are gaining popularity and offer advantages over existing therapeutic strategies. In this perspective, we explore the current state of technological developments, key challenges in the field and potential pathways for translating these innovations into clinical practice.