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Bioelectronic devices and components made from soft, polymer-based and hybrid electronic materials form natural interfaces with the human body. Advances in the molecular design of stretchable dielectric, conducting and semiconducting polymers, as well as their composites with various metallic and inorganic nanoscale or microscale materials, have led to more unobtrusive and conformal interfaces with tissues and organs. Nonetheless, technical challenges associated with functional performance, stability and reliability of integrated soft bioelectronic systems still remain. This Review discusses recent progress in biomedical applications of soft organic and hybrid electronic materials, device components and integrated systems for addressing these challenges. We first discuss strategies for achieving soft and stretchable devices, highlighting molecular and materials design concepts for incorporating intrinsically stretchable functional materials. We next describe design strategies and considerations on wearable devices for on-skin sensing and prostheses. Moving beneath the skin, we discuss advances in implantable devices enabled by materials and integrated devices with tissue-like mechanical properties. Finally, we summarize strategies used to build standalone integrated systems and whole-body networks to integrate wearable and implantable bioelectronic devices with other essential components, including wireless communication units, power sources, interconnects and encapsulation.