Intracortical electrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications.  In general, these electrode devices suffer from reliability abd variability issues that impact their performance on the order of months to years.  The failure mechanisms of these electrodes are understood to be a complex combination of the biological inflammatory tissue response and material failure of the device over time.  Emerging transgenic tools combined with in vivo multi-photon microscopy, functionally evoked electrophysiology, post-mortem multi-channel immunohistochemistry, impedance spectroscopy, scanning electron microscopy, device design, and emerging biomaterial tools have allowed us to examine these mechanisms with an unprecedented level of details.  This task will discuss our current understanding underlying biological processes behind the inflammatory tissue response to cortically implanted devices at the cellular and molecular level.  These findings point to a detailed roadmap for designing next-generation devices that emphasizes the blurring of biology and technology.