Clinicians and investigators have been implanting biomedical devices into patients and experimental animals for centuries. There is a characteristic complex inflammatory response to the presence of the biomedical device with diverse cell signaling, followed by migration of fibroblasts to the implant surface and the eventual walling off of the implant in a collagen capsule. If the device is to interact with the surrounding tissues, the collagen envelope will eventually incapacitate the device or myofibroblasts can cause capsular contracture with resulting distortion, migration, or firmness. This review analyzes the various tactics used in the past to modify or control capsule formation with suggestions for future investigative approaches.