Survival of humanity is likely dependent on our ability to leave Earth and colonise other planetary bodies. However, space environment presents several environmental stressors that prove deleterious to human health, for example high cosmic radiation and prolonged microgravity. As such, a major obstacle preventing long duration space exploration is exponential decline in multiple physiological systems that would ultimately pose a serious risk to astronaut health. There is a need to understand how life responds to the challenges associated with life in space and develop effective countermeasures. However, elucidating mechanistic insight and initial demonstrations of pharmacologic countermeasures against flight-induced health decline are not possible in humans. Utilizing alternate systems remain at the forefront of understanding flight-induced health effects and determining the efficacy of new therapeutic strategies. The microscopic worm C. elegans present several advantages as a model organism. As the first multicellular organism to have its genome sequenced, there exists a wealth of genetic tools available for studying pathways of interest. Sequencing of higher organisms’ genome has shown 35% of C. elegans genes have homologues in humans and at least 42% of human disease-related genes have C. elegans homologues, with essential and highly connected genes being most frequently conserved. Importantly, the architecture of major organs (e.g. muscle) is almost identical between C. elegans and mammals and many of the major molecular signalling and metabolic pathways are present in both systems. C. elegans recapitulate the most consistently observed effects of spaceflight in rodents and astronauts. This worm has set developmental timings, allowing selection of developmental stages for controlled experimentation, which can also be designed for minimal astronaut input to reduce risk of experimental failure. Short generation time (3-4 d) also provide large sample size for studying population level effects of spaceflight in short time frames. Small hardware volume and low up-mass can minimise cost and launch requirements and be considered for inclusion in exploratory missions beyond the Van Allen belts to understand the adaptation/ survivability of life in deep space. C. elegans is, therefore, highly suited to the rapid exploration of novel biological pathways, particularly in the context of the experimental constraints present in spaceflight. We have successfully studied C. elegans adaptation to spaceflight on multiple previous missions on-board the ISS and, in our current flight experiment (Molecular Muscle Experiment, MME; launch Nov. 2018), use C. elegans to establish time, mechanisms of and countermeasures against neuromuscular decline in flight. Helping understand and counter health decline in low Earth orbit and beyond, studies in C. elegans can ultimately help prepare humanity for long-term habitation of space.