Successful application of crosslinking combined with mass spectrometry for studying proteins and protein complexes requires specifically-designed crosslinking reagents, experimental techniques, and data analysis software. Using isotopically-coded (heavy and light) versions of the crosslinker and cleavable crosslinking reagents is analytically advantageous for mass spectrometric applications and provides a handle that can be used to distinguish crosslinked peptides of different types, and to increase the confidence of the identification of the crosslinks.