Cross-linking reagents, chosen based on experimental design and goals, can be utilized in vivo, in cell culture, or in vitro. The resulting protein mixture is digested in solution or after SDS-PAGE separation to reduce sample complexity. Cross-linked peptides can be enriched by chromatography or affinity isolation of tagged cross-links. Samples are analyzed by mass spectrometry, where different specialized algorithms can be utilized for detection and subsequent identification of cross-linked peptides and proteins.