As the number of recombinant cytokines increases, so does our knowledge of their structure and function in different species. The biological cross-reactivity of cytokines from one species on cells from a different species has been reported on in the literature but this information is scattered over many publications and some of it has not yet been published. Comparing sequence information combined with three-dimensional and receptor-binding information (i.e. biological cross-reactivity) in different species provides insight into the underlying rules governing cross-reactivity and conservation. It was observed that there is quite a strict threshold of 60% amino acid identity above which cytokines tend to cross-react. Below this threshold few cytokines cross-react on cells from a different species. When comparing frequencies of reported species cross-reactivities between cytokines belonging to different cytokine-folding families it is obvious that not all cytokines within these folding families are equally cross-reactive. The underlying reason for these differences may lay in the ability of certain folding families to accumulate more mutations and still produce a protein, which is able to fold in the desired tridimensional structure. For example, cytokines belonging to the short 4-alpha-helix bundle can accumulate mutations in the 4-alpha-helices and large loops connecting the 4-alpha-helices and are the least cross-reactive. In contrast, cytokines belonging to the beta-sheet based folds (beta-trefoil and beta-sandwich) are the most cross-reactive and also the most conserved cytokines amongst the different species studied.