Understanding the interactions of proteins with other proteins and/or with drug molecules is essential for understanding the progression of diseases. In this chapter, we present several methods utilizing mass spectrometry (MS) for the analysis of protein-protein, protein-drug, and protein-metal interactions. We describe the analysis of protein interactions with hydrogen exchange MS methods. Hydrogen exchange methods can be used to analyze conformational changes on binding, to estimate dissociation constants, and to locate the sites of interaction/binding between binding partners. We also discuss more direct MS methods, including the analysis of metal ion complexation with proteins.