Future electronics will play a more critical role in people’s lives, as reflected in the realization of advanced human–machine interfaces, disease detection, medical treatment, and health monitoring. The current electronic products are rigid, non-degradable, and cannot repair themselves. Meanwhile, the human body is soft, dynamic, stretchable, degradable, and self-healing. Consequently, it is valuable to develop new electronic materials with skin-like properties that include stretchability, inhibition of invasive reactions, self-healing, long-term durability, and biodegradability. These demands have driven the development of a new generation of electronic materials with high-electrical performance and skin-like properties, among which e-polymers are increasingly being more extensively investigated. This review focuses on recent advances in synthesizing e-polymers and their applications in biointerfaces and organisms. Discussions include the synthesis and properties of e-polymers, the interrelationships between engineered material structures and human interfaces, and the application of implantable and wearable systems for sensors and energy harvesters. The final section summarizes the challenges and future opportunities in the evolving materials and biomedical research field.