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Emerging microsystems such as portable and implantable medical electronics, wireless microsensors and next-generation portable multimedia devices demand a dramatic reduction in energy consumption. The ultimate goal is to power these devices using energy harvesting techniques such as vibration-to-electric conversion or through wireless power transmission. A major opportunity to reduce the energy consumption of digital circuits is to scale supply voltages to 0.5V and below. The challenges associated with ultra-low-voltage design will be presented. These include variation-aware design for logic and SRAM circuits, efficient DC-DC converters for ultra-low-voltage delivery, and algorithm structuring to support extreme parallelism. This paper also addresses micro-power analog and RF circuits, which require the use of application-specific structures and highly digital variation-aware architectures.