In 1999 we reported an important demonstration of a working brain-machine interface (BMI), in which recordings from multiple, single neurons in sensorimotor cortical areas of rats were used to directly control a robotic arm to retrieve a water reward. Subsequent studies in monkeys, using a similar approach, demonstrated that primates can use a BMI device to control a cursor on a computer screen and a robotic arm. Recent studies in humans with spinal cord injuries have shown that recordings from multiple, single neurons can be used by the patient to control the cursor on a computer screen. The promise is that one day it will be possible to use these control signals from neurons to reactivate the patient’s own limbs. However, the ability to record from large populations of single neurons for long periods of time has been hampered because either the electrode itself fails or the immunological response in the tissue surrounding the microelectrode produces a glial scar, preventing single-neuron recording. While we have largely solved the problem of mechanical or electrical failure of the electrode itself, much less is known about the long term immunological response to implantation of a microelectrode, its effect on neuronal recordings and, of greatest importance, how it can be reduced to allow long term single neuron recording. This article reviews materials approaches to resolving the glial scar to improve the longevity of recordings. The work to date suggests that approaches utilizing bioactive interventions that attempt to alter the glial response and attract neurons to the recording site are likely to be the most successful. Importantly, measures of the glial scar alone are not sufficient to assess the effect of interventions. It is imperative that recordings of single neurons accompany any study of glial activation because, at this time, we do not know the precise relationship between glial activation and loss of neuronal recordings. Moreover, new approaches to immobilize bioactive molecules on microelectrode surfaces while maintaining their functionality may open new avenues for very long term single neuron recording. Finally, it is important to have quantitative measures of glial upregulation and neuronal activity in order to assess the relationship between the two. These types of studies will help rationalize the study of interventions to improve the longevity of recordings from microelectrodes.