Confinement and isolation have always confounded the extraordinary endeavor of human spaceflight. Psychosocial health is at the forefront in considering risk factors that imperil missions of 1- to 2-yr duration. Current crewmember selection metrics restricted to behavioral observation by definition observe rather than prevent performance degradation and are thus inadequate when preflight training cannot simulate an entire journey. Nascent techniques to monitor functional and task-related cortical neural activity show promise and can be extended to include whole-brain monitoring. Watching spaceflight crews think can reveal the efficiency of training procedures. Moreover, observing subcortical emotion centers may provide early detection of developing neuropsychiatric disorders. The non-invasive functional neuroimaging modalities electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance imaging (MRI), and near-infrared spectroscopy (NIRS), and highlights of how they may be engineered for spacecraft are detailed. Preflight and in-flight applications to crewmember behavioral health from current generation, next generation, and generation-after-next neuroscience research studies are also described. The emphasis is on preventing the onset of neuropsychiatric dysfunctions, thus reducing the risk of mission failure due to human error.