Formaldehyde is a key fixation reagent. This review explores its application in combination with qualitative and quantitative mass spectrometry (MS). Formalin-fixed and paraffin-embedded (FFPE) tissues form a large reservoir of biologically valuable samples and their investigation by MS has only recently started. Furthermore, formaldehyde can be used to stabilise protein–protein interactions in living cells. Because formaldehyde is able to modify proteins, performing MS analysis on these samples can pose a challenge. Here we discuss the chemistry of formaldehyde cross-linking, describe the problems of and progress in these two applications and their common aspects, and evaluate the potential of these methods for the future.
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