Motions between individual domains are known to play an important role in protein function. Protein cavities at domain interfaces have been suggested to facilitate such movements. Consequently, the cavity morphology in a set of multi-domain proteins has been critically examined. The conformational changes were well characterised by atomic resolution tertiary structures prior to and after domain motions. The results showed that interdomain cavities play a number of specific functional roles by either facilitating, or being otherwise involved with, domain: domain motions. Correspondingly, a higher fraction of cavity surface is observed at domain interfaces as compared to that buried within individual domains. Furthermore, interdomain cavity-forming residues were found to be highly conserved in terms of amino acid residue sequence and volume within their aligned protein families, more so than residues exclusive to the domain interface and intradomain cavities. These results provide substantial evidence of cavities fulfilling a specific functional role in multi-domain proteins.