Intracortical microelectrodes exhibit enormous potential for researching the nervous system, steering assistive devices and functional electrode stimulation (FES) systems for severely paralyzed individuals, and augmenting the brain with computing power. Unfortunately, intracortical microelectrodes often fail to consistently record signals over clinically useful time frames. Biological mechanisms, such as the foreign body response to intracortical microelectrodes and self-perpetuating neuroinflammatory cascades contribute to the inconsistencies and decline in recording performance. The overall goal of this work was to investigate the role of innate immunity signaling in the foreign body response to intracortical microelectrodes. In this dissertation I examined the effect of cluster of differentiation 14 (CD14) inhibition via a systemically administered, small-molecule antagonist, as well as knockout mouse models on intracortical microelectrode recording performance and tissue integration. Mice receiving the small molecule antagonist to CD14 (IAXO-101) exhibited a significant improvement in recording performance over the 16-week experiment. Additionally, CD14 knockout mice exhibited significant improvements in recording performance in the first two weeks after implantation, but not the remainder of the study. These findings suggest that full removal of CD14 is helpful in the first two weeks after implantation, but a limited amount of CD14 signaling may be useful at later time points. Further, we investigated the role of two dominant co-receptors to CD14, Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), in the foreign body response to intracortical microelectrodes. The TLR4 knockout mice exhibited significant decreases in blood-brain barrier permeability at 2 and 16 weeks after implantation, despite exhibiting significantly reduced neuronal survival at 16 weeks after implantation. These results suggest that TLR4 plays a role in the mediation of blood-brain barrier integrity as well as neuroprotective mechanisms, so full removal of TLR4 is also detrimental to chronic integration of intracortical microelectrodes. The TLR2 knockout mice did not exhibit any histological differences from wildtype mice at 2 or 16 weeks, suggesting that TLR2 does not play a major role in the foreign body response to intracortical microelectrodes. The findings of this work suggest the involvement of CD14 and TLR4 in the foreign body response to intracortical microelectrodes. However, implementation of innate immunity inhibition to improve the long-term performance of intracortical microelectrodes requires temporal refinement of inhibition strategies.