With the invention of electrospray ionization and matrix-assisted laser desorption/ionization, scientists employing modern mass spectrometry naturally face new challenges with respect to background interferences and contaminants that might not play a significant role in traditional or other analytical techniques. Efforts to continuously minimize sample volumes and measurable concentrations increase the need to understand where these interferences come from, how they can be identified, and if they can be eliminated. Knowledge of identity enables their use as internal calibrants for accurate mass measurements. This review/tutorial summarizes current literature on reported contaminants and introduces a number of novel interferences that have been observed and identified in our laboratories over the past decade. These include both compounds of proteinaceous and non-proteinaceous nature. In the supplemental data a spreadsheet is provided that contains a searchable ion list of all compounds identified to date.