Beyond CESN and AD, increasing hardware and software efficiency in radiation sensor electronics is a critical step in enabling the capability to solve problems that may not even be known today. Detectors are our “sixth sense” in nuclear nonproliferation and require an integral approach to redefine the half-century-old problem: starting with the radiation sensor itself with technologies alternative to those currently available on the market, then optimizing the light collection using solid state technologies, and finally bringing the new digital methods to signal processing and power/weight optimization of the detectors. Beyond man-made detectors, biological sensors could become a promising tool to aid with detection of proliferation and present a transformative approach to instrumentation.