Heme proteins perform various biological functions ranging from electron transfer, oxygen binding and transport, catalysis, to signaling. Although adopting proper native states is very important for these functions, progresses in representative heme proteins, including cytochrome c (cyt c), cytochrome b5 (cyt b5), myoglobin (Mb), neuroglobin (Ngb), cytochrome P450 (CYP) and heme-based sensor proteins such as CO sensor CooA, showed that various native functions, or new functions evolved, are also closely associated with non-native states. The structure and function relationship of heme proteins in non-native states is thus as important as that in native states for elucidating the precise roles of heme proteins in biological systems.