Copper-64 (t(1/2)=12.7 h; beta+: 17.4%; E(beta+max)=656 keV; beta-: 39%; E(beta-max)=573 keV) has emerged as an important non-standard positron-emitting radionuclide for positron emission tomography imaging of diseased tissues. A significant challenge of working with copper radionuclides is that they must be delivered to the living system as a stable complex that is attached to a biological targeting molecule for effective imaging and therapy. Significant research has been devoted to the development of ligands that can stably chelate (64)Cu, in particular, the cross-bridged (CB) macrocyclic chelators. This review describes the coordination chemistry and biological behavior of (64)Cu-labeled CB complexes.