An information content analysis of protein-binding sites gives a quantitative description of the specificity of the protein, independent of the mechanism of specificity. It gives useful information about the total specificity of the protein and about the individual positions within the binding sites. Information content is consistent with both thermodynamic and statistical analyses of specificity.2,4 When applied to a collection of known binding sites, the description provided may be limited by the sample size or by unknown constraints on those sites. Experimental procedures to determine the information content can give much more reliable measures. A large number of functional sites can be obtained from a much larger pool of randomized potential sites. Quantitative assays for the activity of different sites can be easily incorporated into the analysis, thereby increasing its sensitivity. Both in vitro and in vivo experiments are amenable to information content analysis.