Measuring in a quantitative, statistical sense the degree to which structural and functional information can be``transferred'' between pairs of related protein sequences at various levels of similarity is an essential prerequisite for robust genome annotation. To this end, we performed pairwise sequence, structure and function comparisons on $30,000 pairs of protein domains with known structure and function. Our domain pairs, which are constructed according to the SCOP fold classi®cation, range in similarity from just sharing a fold, to being nearly identical. Our results show that traditional scores for sequence and structure similarity have the same basic exponential relationship as observed previously, with structural divergence, measured in RMS, being exponentially related to sequence divergence, measured in percent identity. However, as the scale of our survey is much larger than any previous investigations, our results have greater statistical weight and precision. We have been able to express the relationship of sequence and structure similarity using more``modern scores,``such as Smith-Waterman alignment scores and probabilistic P-values for both sequence and structure comparison. These modern scores address some of the problems with traditional scores, such as determining a conserved core and correcting for length dependency; they enable us to phrase the sequence-structure relationship in more precise and accurate terms. We found that the basic exponential sequence-structure relationship is very general: the same essential relationship is found in the different secondary-structure classes and is evident in all the scoring schemes. To relate function to sequence and structure we assigned various levels of functional similarity to the domain pairs, based on a simple functional classi®cation scheme. This scheme was constructed by combining and augmenting annotations in the enzyme and¯y functional classi®cations and comparing subsets of these to the Escherichia coli and yeast classi®cations. We found sigmoidal relationships between similarity in function and sequence, with clear thresholds for different levels of functional conservation. For pairs of domains that share the same fold, precise function appears to be conserved down to $40 % sequence identity, whereas broad functional class is conserved to $25 %. Interestingly, percent identity is more effective at quantifying functional conservation than the more modern scores (e.g. Pvalues). Results of all the pairwise comparisons and our combined functional classi®cation scheme for protein structures can be accessed from a web database at