The native structures of proteins are governed by a large number of non-covalent interactions yielding a high specificity for the native packing of structural elements. This allows for the reconstitution of proteins from disconnected polypeptide fragments. The specificity for the native arrangement also enables interchange of structural elements with another identical protein chain resulting in dimers with swapped segments. Proteins are not static structures, but open up repetitively on a timescale of minutes to years depending on the identity of the protein and solution conditions. The open protein may self-close and return to the native state, or it may close with another polypeptide chain leading to 3D domain swapping. The term describes two or more protein molecules swapping identical domains or smaller secondary structure elements. The non-covalent intra-molecular interactions between domains in the monomer are thus broken and restored in the oligomer by identical inter-molecular contacts. This review will discuss 3D domain swapping in relation to protein reconstitution and fibril formation. Examples of reconstituted and domain-swapped proteins will be given. The physiological benefits of 3D domain swapping will be discussed, as well as its role in the evolution of proteins and pathology.