Cleared for Launch: Pre-flight Medical Assessment in the Commercial Spaceflight Era.

Commercial human spaceflight has expanded markedly since 2021, with a growing cohort of civilian participants having undertaken suborbital, orbital free-flyer, and International Space Station visiting-crew missions. Pre-flight medical assessment of this population, however, continues to rely on regulatory guidance that predates the first civilian orbital flight by approximately fifteen years and stratifies eligibility on a single dimension of G-load exposure. The evidence accumulated since on spaceflight-associated neuro-ocular syndrome, on centrifuge-analog tolerance in participants with chronic comorbidities, on the integrated multi-omic findings of recent civilian orbital missions, and on the new mission profiles introduced by the Axiom and Polaris Dawn programs has not been incorporated into a unified evaluation framework. In this narrative review, the aerospace-medicine and clinical literature of the past two decades is synthesized within a framework that distinguishes mission-related background factors (including acceleration, microgravity, spaceflight-associated neuro-ocular syndrome, ionizing radiation, and cabin environment) from participant-related factors (comprising age, sex, reproductive status, and cardiopulmonary, metabolic, and oncological comorbidity). The documented cohort spans 18 to 90 years of age, with the extremes confined to suborbital flights. The orbital free-flyer subset (n=12 across Inspiration4, Polaris Dawn, and Fram2) ranges from approximately 29 to 63 years, and the International Space Station (ISS) visiting-crew subset (n=12 civilian participants across Axiom AX-1 through AX-4, excluding career-astronaut commanders) from 33 to 71 years. Documented comorbidities include treated coronary artery disease, paroxysmal atrial fibrillation, type 2 diabetes mellitus, obstructive sleep apnea, and prior oncological conditions. Based on the available evidence, a clinical routine is proposed, organized across three assessment tiers - a universal baseline (Tier 1), an indication-driven system-specific evaluation (Tier 2), and a mission-class-specific evaluation (Tier 3) - and distributed along a four-step pathway from 90 days before flight to the day of launch. The proposed workflow may serve as an operational starting point, although prospective validation will be required as the commercial era generates additional data on participants, mission profiles, and clinical outcomes.