Cross‐strand disulphides (CSDs) are unusual bonds that link adjacent strands in the same β‐sheet. Their peculiarity relates to the high potential energy stored in these bonds, both as torsional energy in the highly strained disulphide linkage and as deformation energy stored in the sheet itself. CSDs are relatively rare in protein structures but are conspicuous by their presence in proteins that are involved in cell entry. The finding that entry of botulinum neurotoxin and HIV into mammalian cells involves cleavage of CSDs suggests that the activity of other cell entry proteins may likewise involve cleavage of these bonds. We examine emerging evidence of the involvement of these unusual disulphides in cell entry events. BioEssays 26:73–79, 2004. © 2003 Wiley Periodicals, Inc.