We propose to develop a new generation of mass spectrometric instruments with vastly increased sensitivity, approaching the single molecule level; greatly enhanced capability for the analysis of complex mixtures and multisubunit protein complexes. The research presented here focuses on development of a new time-of-flight mass spectrometer which utilizes single charged droplets as ion sources in combination with an aerodynamic lens to focus the ions onto the center axis of the time of flight region of the mass spectrometer. Single droplets will be generated by a piezoelectric dispenser and transmitted through an aerodynamic lens where they will be desolvated to produce analyte ions. The aerodynamic lens system will replace the standard nozzle-skimmer and collisional cooling systems commonly employed in ESI-TOF. The fact that the ions will travel along a single defined trajectory, rather than along a multitude of trajectories as in conventional electrospray, will permit the collection efficiency of the ions into the mass spectrometer to be greatly increased. Ions exiting the aerodynamic lens will be electrostatically accelerated and time-of-flight mass analyzed as in conventional matrix assisted laser desorption ionization (MALDI) mass spectrometry. Calculations of the increase in detection efficiency that in theory is attainable with this approach suggest that as much as a 10exp12 fold increase could be realized; although practical considerations may limit the achievable increase, it seams clear that a very substantial sensitivity gain is to be expected. Additionally, the proposed instrument greatly simplifies the spectrometer design which should make possible the construction of a simple, robust, and cost effective mass spectrometer.