Microelectrode arrays placed in the nervous system to directly interface with neurons or monitor neurochemicals, have tremendous research and clinical significance. Current arrays experience chronic failure including signal drift and degradation due to the biochemical, mechanical and electrical mismatch between the artificial device and brain tissue. Several biomaterial strategies are being investigated towards a seamless sensor-tissue interface. The first strategy is to camouflage the abiotic implant with biomolecules. A neural adhesion molecule L1 has been coated onto the implant surface showed to improve neuronal growth on and around the implant and reduce inflammatory tissue response and scarring. Secondly, therapeutics to modulate the host tissue responses such as inflammation, degeneration, BBB breach and oxidative stress, have been delivered. Thirdly, new implant materials and designs are being developed that reduces the form factor and matches the mechanical properties of the brain. An elastomeric electrically conductive polymer blend is synthesized that has the mechanical modules similar to that of brain tissue. Soft electrodes made of the new materials showed much better integration with the host tissue compared to the stiff wires. The ultimate solution to a reliable in vivo sensor may be a combinatorial approach that takes advantage of multiple strategies discussed above and beyond.