For the analysis of protein-protein interactions and protein conformations, cross-linking coupled with mass spectrometry (CXMS) has become an essential tool in recent years. A variety of cross-linking reagents are used to covalently link interacting amino acids to identify protein-binding partners. The spatial proximity of cross-linked amino add residues is used to elucidate structural models of protein complexes. The main challenges for mapping protein-protein interaction are low stoichiometry and low frequency of cross-linked peptides relative to unmodified linear peptides as well as accurate and efficient matches to corresponding peptide sequences with low false discovery rates for identifying the site of cross-link. We evaluate the current state of chemical cross-linking and mass spectrometry applications with the special emphasis on the recent development of informatics data processing and analysis tools that help complexity of interpreting CXMS data. This article is part of a Special Issue entitled:Physiological Enzymology and Protein Functions. (C) 2015 Elsevier B.V. All rights reserved.