A great number of active centers in proteins and enzymes contain transition metals. Each metal imposes specific catalytic properties on the protein which could not be achieved when employing a different metal. The special role and characteristic reactivity of coordinated copper is illustrated by looking at the evolutionary aspects of copper proteins. The evolution of copper-binding sites is closely linked to that of copper proteins. Copper centers have evolved according to various principles, similar to the evolutionary development of proteins and enzymes. Three basic principles may be observed: the copper-binding centers of metallothioneins and type 1 copper centers developed in non-metal proteins; the transformation of the metal-binding centers of iron or manganese proteins led to the development of the type 2 copper centers; and the trinuclear copper-binding centers of the blue oxidases were formed by alterations and recombinations of type 1 copper centers. Simple, although as yet unknown, mononuclear copper centers gave rise to the type 3 copper-binding sites of the hemocyanins and tyrosinases, as well as to the Cu A-and CUB-centers of the cytochrome oxidases and N20reductase. According to this assignment, copper proteins containing either type 1 copper, type 3 copper, CUA-centers, or CUB-centers share a common ancestor. They developed at least in part by divergent evolution. Type 2 copper proteins are the products of convergent evolution and, consequently, show little or no phylogenetic homology.