A method of identifying binding compounds that have equivalent or improved affinities to a ligand as that of a reference binding compound, the method comprising the steps of: reacting under binding conditions a ligand with a library of binding compounds, the library comprising candidate binding compounds and a reference binding compound, wherein each candidate binding compound and the reference binding compound comprise a protein encoded by a nucleotide sequence and wherein each of the candidate binding compounds of the library is obtained by varying amino acids at one or two locations at a time with respect to the reference binding compound wherein each of the one or two locations is selected from 10 to 250 amino acid locations in the reference binding compound or one location is selected from 1 to 500 amino acid locations in the reference binding compound; determining the nucleotide sequences of a sample of binding compounds forming complexes with the ligand; determining the nucleotide sequences of a sample of binding compounds free of ligand or a sample of binding compounds from the library; wherein values for numbers of binding compounds in said samples have coefficients of variation of ten percent or less; ordering the nucleotide sequences of the binding compounds in accordance with the affinities of their respective binding compounds for the ligand, wherein the affinities are determined for each binding compound by comparing the number of times a nucleotide sequence is identified with the binding compound forming complexes with the ligand and the number of times the same nucleotide sequence is identified with the binding compound free of the ligand or the number of the same nucleotide sequence identified in the sample of binding compounds from the library; and identifying among the ordering of nucleotide sequences those nucleotide sequences that encode candidate binding compounds having affinities that are equivalent to or greater than that of the nucleotide sequence encoding the reference binding compound. reacting under binding conditions a ligand with a library of binding compounds, the library comprising candidate binding compounds and a reference binding compound, wherein each candidate binding compound and the reference binding compound comprise a protein encoded by a nucleotide sequence and wherein each of the candidate binding compounds of the library is obtained by varying amino acids at one or two locations at a time with respect to the reference binding compound wherein each of the one or two locations is selected from 10 to 250 amino acid locations in the reference binding compound or one location is selected from 1 to 500 amino acid locations in the reference binding compound; determining the nucleotide sequences of a sample of binding compounds forming complexes with the ligand; determining the nucleotide sequences of a sample of binding compounds free of ligand or a sample of binding compounds from the library; wherein values for numbers of binding compounds in said samples have coefficients of variation of ten percent or less; ordering the nucleotide sequences of the binding compounds in accordance with the affinities of their respective binding compounds for the ligand, wherein the affinities are determined for each binding compound by comparing the number of times a nucleotide sequence is identified with the binding compound forming complexes with the ligand and the number of times the same nucleotide sequence is identified with the binding compound free of the ligand or the number of the same nucleotide sequence identified in the sample of binding compounds from the library; and identifying among the ordering of nucleotide sequences those nucleotide sequences that encode candidate binding compounds having affinities that are equivalent to or greater than that of the nucleotide sequence encoding the reference binding compound.