OBJECTIVES: This analysis aimed to: 1) identify and assess potential innovations in measles vaccination, and 2) pilot test a methodological framework using prospective cost-effectiveness analysis based on measles transmission mathematical modeling to inform global investment decisions. METHODS: Potential innovations available by 2020 were identified based on the literature and interviews with experts. Two sets of models were constructed to explore cost-effectiveness scenarios and the sensitivity of results: 1) a dynamic, compartmental measles transmission model estimated for six developing countries, and 2) an aggregate global cost model to project the volume of measles vaccine use and the impact of any per dose cost savings over the period 2010-49 in the 84 countries currently purchasing single-antigen measles vaccine. RESULTS: Four innovations were assessed: 1) needle-free, jet injection of the current vaccine; 2) aerosolized delivery of the current vaccine via nebulizer; 3) inhalable, more thermostable dry powder vaccine; and 4) DNA vaccine for early administration (two doses). For the six countries, the health outcomes impact of the new technologies on absolute disease burden would be beneficial, but minimal compared to the conventional vaccine at target coverage levels. With a projected 4.2 billion births over this period, aggregate, global discounted cost savings—due to reduced wastage and sharps disposal— were projected as: $98 million for jet injector, $154 million for the aerosol, and $689 million for the inhalable dry powder. The DNA vaccine would increase spending by $3.9 billion. CONCLUSIONS: Three potential measles vaccination technologies on the horizon are projected to be net cost-saving—from a global perspective—over the long-term. Although difficult to demonstrate pre-launch, developers expect these innovations to improve coverage and reduce disease burden. Decisions about additional investments will require research on the costs and likelihood of success in development as well as the costs and barriers to uptake, including system readiness.