The alternative oxidases (AOXs) are ubiquinol-oxidoreductases that are members of the diiron carboxylate superfamily. They are not only ubiquitously distributed within the plant kingdom but also found in increasing numbers within the fungal, protist, animal and prokaryotic kingdoms. Although functions of AOXs are highly diverse in general, they tend to play key roles in thermogenesis, stress tolerance (through the management of radical oxygen species) and the maintenance of mitochondrial and cellular energy homeostasis. The best structurally characterised AOX is from Trypanosoma brucei. In this review, we compare the structure of AOXs, created using homology modelling, from many important species in an attempt to explain differences in activity and sensitivity to AOX inhibitors. We discuss the implications of these findings not only for future structure-based drug design but also for the design of novel AOXs for gene therapy.