State-of-the-art structural mass spectrometry-based proteomics is often accomplished by using cross-linkers to covalently bind two or more amino-acid groups. This strategy is complementary to classical structural biology and therefore broadens the toolset for analyzing protein and protein-protein complex structures. One of the greatest challenges in identifying cross-linked peptides in complex protein mixtures is computationally dealing with the large search space, which grows quadratically with each peptide included in the sequence database. The Spectrum Identification Machine for Cross-Linked Peptides (SIM-XL) software uses an algorithm that overcomes this limitation by capitalizing on experimental features that allow it to effectively address the massive combinatorial problem at hand, and presents the results in a user-friendly manner. Thus, SIM-XL is recommended for studies dealing with protein structure and protein-protein interaction in either simple or complex protein mixtures. SIM-XL also allows the sharing of results through PRIDE by exporting them in the mzIdentML format.