Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic core, and C-terminal domains interact in the holoenzyme remains obscure. Catalytically active recombinant IN can exist in a dynamic equilibrium of monomers, dimers, tetramers, and higher order species. Numerous studies indicate that the enzyme functions as a multimer, minimally a dimer. The IN proteins from HIV-1 and ASV have been studied most carefully with respect to the structural basis of catalysis. Although the active site of ASV IN does not undergo significant conformational changes on binding the required metal cofactor, that of HIV-1 IN does. The reversible, metal-induced conformational change in HIV-1 IN impairs the binding of some anti-HIV-1 IN monoclonal antibodies to the enzyme and results in differential susceptibility of the protein to proteolysis. This active site-mediated conformational change reorganizes the catalytic core and C-terminal domains and appears to promote an interaction that is favorable for catalysis. Other metal-dependent structural changes in HIV-1 IN include the promotion of interactions between the N terminal and the catalytic core domains and the induction of tetramers by zinc ions. The end result of these metal-induced changes is apparently the induction of an activated holoenzyme that can form a stable ternary integrase-metal-DNA complex. These structural changes, which appear to be crucial for optimum catalysis in HIV-1 IN, do not occur in ASV IN. The structural changes observed in HIV-1 IN may serve to recruit the catalytic machinery in this enzyme to a conformation that is native for ASV IN.