Native mass spectrometry (MS) is a powerful tool for the characterization of protein structure, stoichiometry, and stability, made possible by the use of electrospray ionization (ESI) to gently transfer proteins from solution to the gas phase. However, nonspecific aggregation can occur during ESI, which may lead to inaccurate determinations of biomolecular complex stoichiometry and adds ambiguity towards the existence of small molecule clusters in solution. This work resolves a long standing debate in the MS community by using submicron diameter emitters to investigate the abundance of small serine clusters in solution and to compare the physical properties of these clusters when formed from solution or by dissociation of even larger clusters in the gas-phase, demonstrating that the homochiral serine octamer exists in solution and that the unusually high abundance of the octamer observed in prior ESI-MS experiments is due to activation/dissociation of larger clusters in the MS instrument. Submicron diameter emitters also enable the measurement of protein charge-state distributions from nonvolatile buffers, but there are no standardized protocols for their fabrication or use. This work contains a detailed protocol for fabricating nanoelectrospray (nESI) emitters with diameters between 200 nm – 2.5 µm and guidelines for their use. To date, this is the only systematic characterization of the effect of instrument parameters on electrospray emitter diameter and morphology. This work also investigates the effect of electrospray voltage and emitter tip size on ESI droplet sizes and describes unique ionization phenomena that result from corona discharge at the tip of submicron diameter nESI emitters. In native MS, compact protein structures exhibit low extents of charging whereas highly elongated conformations, such as denatured forms, exhibit higher extents of charging. Protein thermal denaturation curves can be obtained from MS data by plotting the average charge state as a function of solution temperature. Protein melting temperatures (T_m) can be extracted from these data by fitting with a two-state model. However, thermal equilibration of typical “variable-temperature ESI” sources requires 1 – 3 minutes at each temperature. These long thermal equilibration times are not compatible with solution-phase separations and can result in protein aggregation that clogs ESI emitters. Using an infrared laser to directly heat only ~200 pL of solution at the tip of nESI emitters, this work describes an apparatus to circumvent these issues termed laser heated ESI (LH-ESI). LH-ESI can be used to obtain melting curves and T_m values for individual proteins in a mixture in less than 45 seconds. Protein molecules are directly exposed to heat from the laser beam for only ~140 ms, enabling the simultaneous measurement of melting curves for the apo- and ligand-bound forms of bovine carbonic anhydrase II, an aggregation-prone protein, and the first observation of a ~6.4 °C stabilizing effect on the T_m due to bicarbonate ligand binding. LH-ESI shows significant promise for the high-throughput characterization of protein thermal stabilities and protein-ligand interactions through fast melting curve measurements that enable a higher number of samples to be analyzed per day. Biotherapeutics, as well as proteins involved in neurodegenerative disease, can undergo aggregation that results in the formation of oligomers that may be conformationally heterogeneous and spread across a wide range of mass and size. These aggregates are difficult to characterize using conventional mass spectrometry due to the limited transmission and loss of charge state resolution for large biomolecules, as well as extensive m/z overlap of elongated species. Charge detection mass spectrometry (CDMS) circumvents these issues by separately measuring the mass and charge of individual ions. This work describes the development of CDMS methods to characterize the oligomers formed from biotherapeutic monoclonal antibodies during purification, freeze/thaw cycles, or heat stress. Similar experiments performed on a model protein, bovine serum albumin (BSA), investigate how protein monomer concentration and the presence of aggregation inhibitors affects the oligomer size and shape after heat stress. These experiments show, for the first time, the conformational heterogeneity of small protein oligomers, how aggregation inhibitors or protein concentration affects the aggregation pathway and kinetics at the individual oligomer level, and demonstrate the promise of CDMS as a high-throughput technique for characterizing the effect of drugs or additives on the aggregation of proteins related to neurodegenerative disease and biotherapies.