Cognitive-performance and motor-performance activities in multi-task, high-workload environments were assessed during astronaut performance in space flight and in isolation. Data was collected in microgravity on the International Micro-gravity Laboratory (IML) space shuttle mission (STS-42), and the Canadian Astronaut Program Space Unit Life Simulation (CAPSULS) mission offered an ideal opportunity to collect data for individuals in extreme isolation to complement the space flight data using similar hardware, software, and experimental protocols. The mental workload and performance experiment (MWPE) was performed during the IML-1 space flight mission, and the memory processes and motor control (MEMO) experiment was performed during the CAPSULS isolation mission. In both experiments, short-term exhaustive memory and fine motor control associated with human-computer interaction was studied. Memory processes were assessed using a Sternberg-like exhaustive memory search containing 1, 2, 4, or 7 letters. Fine motor control was assessed using velocity-controlled (joystick) and position-controlled (trackball) computer input devices to acquire targets as displayed on a computer screen. Subjects repeated the tasks under two conditions that tested perceptual motor adaptation strategies: 1) During adaptation to the microgravity environment; and 2) While wearing left-right reversing prism goggles during the CAPSULS mission. Both conditions significantly degraded motor performance but not cognitive performance. The data collected during both the MEMO experiment and the MWPE experiments enhance the knowledge base of human interface technology for human performance in extreme environments.