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As humans embark on longer and deeper missions into space, it is crucial to understand how spaceflight impacts the immune system. Decades of discoveries, bolstered by recent multiomic analyses, have identified key immune processes that are affected by the spaceflight environment. These findings form the foundations of the emerging field of 'astroimmunology'. Spaceflight stressors - such as microgravity and galactic cosmic radiation - and other mission-associated variables, including psychological stress and abnormal circadian rhythms, can disrupt or adversely affect immune cell biology. In addition, spaceflight alters host-microbiome interactions, which can increase susceptibility to opportunistic pathogens and viral reactivation. Although ground-based analogues for human spaceflight have provided insights into these stressors individually, their combined effects during spaceflight remain less understood. This Review explores our current knowledge of the effects of spaceflight stressors on the immune system and the clinical implications for human space exploration. It also highlights current and developing countermeasures, including machine-learning approaches, advanced monitoring technologies and standardized biobanking, that can facilitate research into the impact of spaceflight on the immune system. Looking ahead, progressing from low Earth orbit missions to long-term missions to the Moon, Mars and beyond will introduce new challenges, including increased radiation, variable gravity and regolith exposure. We discuss these prospective challenges and outline potential preventive and mitigative strategies for sustaining immune health to enable safe and effective space exploration and habitation of distant worlds.