Antibodies are extremely diverse with respect to their specificities and affinities for target molecules. Despite rigorous selection, some antibodies are cross-reactive whereby they recognize their natural antigens along with other molecules. In this review, we discuss our efforts toward understanding the cross-reactivity of selected immunoglobulins. Investigations that are discussed employed screens of combinatorial peptide libraries, crystallography of ligand-protein complexes, and computer-based peptide docking simulations. In the first example, two different antibodies (NC6.8 and NC10.14) bound the same trisubstituted guanidine (NC174) with similar affinities, but utilized predominantly dissimilar binding strategies. However, there was one common binding strategy, in which the cyanophenyl portion of NC174 was inserted end-on into the binding crevices of the NC6.8 and NC10.14 antibodies. In the second example, scanning of peptide libraries and X-ray crystallography were used to design and test syn thetic peptides for binding to the Mcg L chain dimer. Again, end-on insertion was favored for all peptides larger than dipeptides in the voluminous Mcg binding cavity. Finally, automated docking was used for rapid predictions of complexes for the Fv molecule from a broadly cross-reactive human IgM (Mez) and nearly two thousand peptides. Certain amino acids, including the aromatic residues Trp and Phe, functioned as anchoring groups in automated docking. Anchoring groups acted in most of the peptides that were otherwise accommodated by a variety of binding strategies in the docked complexes. We suggest that anchoring of at least a portion of a ligand in a binding site is a common mechanism for antibody recognition.