The conformation and post-translational modification (PTM) of a protein is critically important to its function. Mass spectrometry has been increasingly utilized to analyze both of these attributes. Acidic PTMs, like phosphorylation and sulfation however, present significant obstacles to analysis. Here, I present a series of techniques to overcome these issues and improve the annotation of these vital modifications. Lastly, I discuss the use of MS-based techniques for the analysis of therapeutic protein conformation.