The past two decades have seen unprecedented progress in the development of novel materials, form factors, and functionalities in neuroimplantable technologies, including electrocorticography (ECoG) systems, multielectrode arrays (MEAs), Stentrode, and deep brain probes. This review highlights the key considerations for the development of such devices intended for acute implantation and chronic use, from the perspective of biocompatible hybrid materials incorporation, conformable device design, implantation procedures, and mechanical and biological risk factors. These topics are connected with the role that the US Food and Drug Administration (FDA) plays in its regulation of neuroimplantable technologies based on the above parameters. Existing neuroimplantable devices and efforts to improve their materials and implantation protocols are first discussed in detail. Then the effects of device implantation with regards to biocompatibility and brain heterogeneity are explored. Topics examined include brain-specific risk factors, such as bacterial infection, tissue scarring, inflammation, and vasculature damage, as well as efforts to manage these dangers through emerging hybrid, bioelectronic device architectures. The current challenges of gaining clinical approval by the FDA—in particular, its relationship to biological, mechanical, and materials risk factors—are summarized. This work concludes by discussing the available regulatory pathways to accelerate next-generation neuroimplantable devices to market.