Pandemic preparedness is weakened by uncertainty about the relative importance of influenza transmission modes, particularly airborne droplet nuclei (aerosols). A human-challenge transmission trial in a controlled environment was conducted to address this uncertainty. Healthy, seronegative volunteer ‘Donors’ (N=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2) and exposed to seronegative ‘Recipients’ randomized to intervention (N=40) or control (N=35) groups. Intervention recipients wore face shields and hand sanitized frequently to limit large droplet and contact transmission. A transmitted infection, confirmed by serology in a control recipient, yielded a 1.3% SAR overall. This was significantly less than the expected 16% SAR (p <0.001) based on a proof-of-concept study that used half as many Donors and exposure days. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols. The extent to which Donor viral shedding was similar to that of mild, natural infections and may be useful for studying transmission was investigated. The only available aerosol shedding comparison data comes from a population of adults with influenza A H3 infection enrolled on the basis of febrile illness plus cough or sore throat, or positive Quidel QuickVue rapid test (N=83). Systematic differences in case selection compared with Donors yielded more severe cases and introduced bias. To account for differences in illness severity, propensity score matching, stratification, and inverse weighting ultimately demonstrated that the experimental and naturally infected groups were too different to compare without bias. While acknowledging the uncertainty in the generalizability of the current challenge model, observed aerosol shedding and CO2 were used in the rebreathed-air version of the Wells-Riley equation to compute average quantum generation rates (95% CI) 0.029 (0.027, 0.03) and 0.11 (0.088, 0.12) per hour for infected Donors and fine aerosol shedding Donors, respectively. Donors shed 1.4E+5 (1.0E+5, 1.8E+5) airborne viral RNA copies per quantum (ID63). This dissertation provides evidence for airborne transmission, presents a methodology for estimating an airborne dose, and suggests a role for building ventilation in reducing risk and the need for future observational studies to evaluate transmission modes in non-experimental settings with greater generalizability.