Monitoring and modulating the diversity of signals used by neurons and glia in a closed-loop fashion is necessary to establish causative links between biochemical processes within the nervous system and observed behaviors. As developments in neural-interface hardware strive to keep pace with rapid progress in genetically encoded and synthetic reporters and modulators of neural activity, the integration of multiple functional features becomes a key requirement and a pressing challenge in the field of neural engineering. Electrical, optical and chemical approaches have been used to manipulate and record neuronal activity in vivo, with a recent focus on technologies that both integrate multiple modes of interaction with neurons into a single device and enable bidirectional communication with neural circuits with enhanced spatiotemporal precision. These technologies not only are facilitating a greater understanding of the brain, spinal cord and peripheral circuits in the context of health and disease, but also are informing the development of future closed-loop therapies for neurological, neuro-immune and neuroendocrine conditions.