 Abstract soft and stretchable electronics have emerged as highly promising tools for biomedical diagnosis and biological studies, as they interface intimately with the human body and other biological systems. However, most stretchable electronic materials and devices still have Young's modulus orders of magnitude higher than soft bio tissues, which limits their conformability and long-term biocompatibility. To address this issue, researchers have developed a design strategy of soft interlayers for allowing the use of existing stretchable materials of relatively high moduli to versitally realize stretchable devices with ultra low tissue level moduli. This has been achieved by creating ultra soft devices with the soft interlayer design, which realizes electrophysiological recording on an isolated heart with high adaptability, spatial stability, and minimal influence on ventricle pressure. Additionally, in vivo biocompatibility tests demonstrate the benefit of suppressing foreign body responses for long-term implantation. With its general applicability to diverse materials and devices, this soft interlayer design overcomes the material level limitation for imparting tissue level softness to a variety of bio-electronic devices. This article was authored by Young Lee, Nan Lee, Wei Liu, and others. We are article.tv, links in the description below.