This chapter discusses the complex boundary between neural tissue and in vivo implanted devices. The new generation of active implantable devices employs microelectronic circuits for in situ signal processing and amplification. Insertion methods and empirical models of the interface between deep brain electrodes and neural tissue are examined, with a detailed analysis of the influence of electrode shape, and distribution of anodes and cathodes. Current limitations include the invasive brain surgery, the risks associated with local bleeding, infection, skin erosion at the site of entry, electrode migration, wire break, electric shocking, device malfunctioning, and limited battery lifetime. There are also a number of psychiatric concerns. Examples of brain prosthetic designs are explored alongside descriptions of efforts to minimize electrical interfacial impedance, material toxicity issues, mechanical strain, and local inflammatory response for chronic implantation, while maximizing stability. Neuro‐engineering applications such as motor cortex prostheses, robotic and computerized hybrid assistive limbs, peripheral neural microprobes and multisite microelectrodes arrays adapted for brain implantation are investigated. Ambitious projects to replace entire damaged brain components and the state‐of‐the‐art in retinal prosthesis devices are described.