Ferredoxin (flavodoxin)-NADP(H) reductases (FNRs) are ubiquitous flavoenzymes that deliver NADPH or low potential one-electron donors (ferredoxin, flavodoxin, adrenodoxin) to redox-based metabolisms in plastids, mitochondria and bacteria. Two great families of FAD-containing proteins displaying FNR activity have evolved from different and independent origins. The enzymes present in mitochondria and some bacterial genera are members of the structural superfamily of disulfide oxidoreductases whose prototype is glutathione reductase. A second group, comprising the FNRs from plastids and most eubacteria, constitutes a unique family, the plant-type FNRs, totally unrelated in sequence with the former. The two-domain structure of the plant family of FNR also provides the basic scaffold for an extended superfamily of electron transfer flavoproteins. In this article we compare FNR flavoenzymes from very different origins and describe how the natural history of these reductases shaped structure, flavin conformation and catalytic activity to face the very different metabolic demands they have to deal with in their hosts. We show that plant-type FNRs can be classified into a plastidic class, characterised by extended FAD conformation and high catalytic efficiency, and a bacterial class displaying a folded FAD molecule and low turnover rates. Sequence alignments supported this classification, providing a criterion to predict the structural and biochemical properties of newly identified members of the family.