The explosive growth of the modern microelectronics field opens new horizons for the development of new lightweight, low power, and smart spacecraft and science instrumentation systems in the new millennium explorations. Although this growth is mostly driven by the commercial need for low power, portable and computationally intensive products, the applicability is obvious in the space sector. The additional difficulties needed to be overcome for applicability in space include radiation hardness for total ionizing dose and single event effects (SEE), and reliability. Additionally, this new capability introduces a whole new philosophy of design and R&D, with strong implications in organizational and inter-agency program management. One key component specifically developed towards low power, small size, highly autonomous spacecraft systems, is the smart sensor remote input/output (TRIO) chip. TRIO can interface to 32 transducers with current sources/sinks and voltage sensing. It includes front-end analog signal processing, a 10-bit ADC, memory, and standard serial and parallel I/Os. These functions are very useful for spacecraft and subsystems health and status monitoring, and control actions. The key contributions of the TRIO are feasibility of modular architectures, elimination of several miles of wire harnessing, and power savings by orders of magnitude. TRIO freely operates from a single power supply 2.5– 5.5 V with power dissipation <10 mW . This system on a chip device rapidly becomes a NASA and Commercial Space standard as it is already selected by thousands in several new millennium missions, including Europa Orbiter, Mars Surveyor Program, Solar Probe, Pluto Express, Stereo, Contour, Messenger, etc. In the Science Instrumentation field common instruments that can greatly take advantage of the new technologies are: energetic-particle/plasma and wave instruments, imagers, mass spectrometers, X-ray and UV spectrographs, magnetometers, laser rangefinding instruments, etc. Common measurements that apply to many of these instruments are precise time interval measurement and high resolution read-out of solid state detectors. A precise time interval measurement chip was specially developed that achieves ∼100 ps (×10 improvement) time resolution at a power dissipation ∼20 mW (×50 improvement), dead time ∼1.5 μs (×20 improvement), and chip die size 5 mm×5 mm versus two 20 cm×20 cm doubled sided boards. This device is selected as a key enabling technology for several NASA particle, delay line imaging, and laser range finding instruments onboard (NASA Image, Messenger, etc. missions). Another device with universal application is radiation energy read-out from solid state detectors. Multi-channel low-power and end-to-end sensor input—digital output is key for the new generation instruments. The readout channel comprises of a Charge Sensitive Preamplifier with a target sensitivity of ∼1 KeV FWHM at 20 pf detector capacitance, a Shaper Amplifier with programmable time constant/gain, and an ADC. The read-out chip together with the precise time interval chip comprises the essential elements of a common particle spectroscopy instrument. To mention some more applications fast-signal acquisition—and digitization is a very useful function for a category of instrument such as mass spectroscopy and profile laser rangefinding. The single chip approach includes a high bandwidth preamplifier, fast sampling ∼5 ns , analog memory ∼10K locations, 12-bit ADC and serial/parallel I/Os. The wealth of the applications proves the advanced microelectronics field as a key enabling technology for the new millennium space exploration.