Immune system deregulation has been demonstrated to occur during and immediately following spaceflight. Several animal models have been used to study this phenomenon because of the limited availability of human subjects in space as well as of the need to carry out experiments requiring samples and experimental conditions that cannot be performed using humans. Here, we review major spaceflight-induced microbial and immunological modifications, some of the existing hardware developed to host amphibians in a space station and immunological information provided by space experiments performed with Pleurodeles waitl as an animal model. These data show that the urodele amphibian P. waftl fulfills many technical requirements associated with spaceflight experimentation and that this model is interesting to improve our understanding of the immunosuppressive effects of spaceflight, data required for the preparation of future deep-space missions.