Vaporization of low-boiling point droplets has numerous applications in combustion, process engineering, and in recent years, in clinical medicine. However, the physical mechanisms governing the phase conversion are only partly explained. Here, we show that an acoustic resonance can arise from the large speed of sound mismatch between a perfluorocarbon microdroplet and its surroundings. The fundamental resonance mode obeys a unique relationship kR∼0.65 between droplet size and driving frequency that leads to a threefold pressure amplification inside the droplet. Classical nucleation theory shows that this pressure amplification increases the nucleation rate by several orders of magnitude. These findings are confirmed by high-speed imaging performed at a timescale of 10 ns. The optical recordings demonstrate that droplets exposed to intense acoustic waves generated by interdigital transducers nucleate only if they match the theoretical resonance size.