<p dir="ltr">Multiply-charged ions of intact biomolecules generated from electrospray ionization (ESI) have drawn researchers' interest in the field of native mass spectrometry (MS) for decades because these ions carry mass and charge information of the intact molecules and interactions among different units. However, the confinement of multiple charge states in a narrow range of <i>m/z</i> makes mass and charge assignments challenging, especially for analytes with a mass greater than 100 kDa. Gas-phase ion/ion reactions have proven to be powerful techniques that facilitate the interpretation of mass spectra of natively sprayed macromolecular analytes by manipulating the masses and charges of ions detected.</p><p dir="ltr">The proton-transfer reaction (PTR) is the most used gas-phase ion/ion reaction method. It utilizes perfluorinated PTR reagents to "grab" protons away from the analyte ions, thereby reducing their charges. A novel charge state manipulation technique called "ion parking," based on PTR, has been developed. In this method, ion signals are accumulated to one or a range of charge states by selectively inhibiting reactions between the target charge state and the PTR reagents via resonance excitation.</p><p dir="ltr">The multiply-charged ion attachment (MIA) reaction is another gas-phase ion/ion reaction approach. It utilizes the significant <i>m/z</i> displacement caused by the attachment of multiply-charged reagent ions, and it has been proven useful for mass analysis of heterogeneous macromolecular analytes with a mass greater than 1 MDa.</p><p dir="ltr">All gas-phase ion/ion reaction techniques require mutual storage of ions in opposite polarities within an electrodynamic quadrupole ion trap, such as a 3D quadrupole ion trap (QIT) or a linear quadrupole ion trap (LIT). Electrodynamic ion traps use high-voltage (HV) drive radio frequencies (RF) to trap ions in a quadrupolar field, typically employing a sinusoidal waveform (sine wave). A digital quadrupole ion trap (DIT) is an unconventional electrodynamic ion trap that uses a digital waveform (square wave) as the drive RF. The high agility of square waves makes DIT an ideal mass analyzer for studying high <i>m/z</i> ions resulting from gas-phase ion/ion reactions. This dissertation describes the development of a novel home-built digital dual-trap mass spectrometer and ion/ion chemistry studies of large biomolecules within the instrument.</p>