Abstract: A system for multi-stage differential mobility spectrometer (multi-stage DMS) and the method of operating and using the same are described. Ions produced in an ionization source are introduced into the separation region of multi-stage DMS, which includes at least two DMS stages. Each DMS stage is configured to generate separation and compensation fields to characterize, separate, or select ion species. The separation region further includes ion alteration stages which are placed between various adjacent stages of multi-stage DMS. Alteration of ions can be both chemical and physical. Ions which are separated, altered, and selectively passed by all DMS stages of multi-stage DMS are then measured or further characterized by the Faraday plate detectors or a mass spectrometer.