This work involved the advancement and optimisation of a solid phase N to C peptide synthesis strategy employing Tri-tert.Butoxysilyl esters and its application to generate peptides containing modified C-termini and modified peptide bonds including urea and reduced peptide bonds. In addition, peptide combinatorial library techniques were developed with a unique bead binding assay and a sequencing/ligand identification method capable of determining phosphotyrosine-peptidyl-resin sequences incorporated into the formation of a peptide library containing over one million 6-mer phosphotyrosine-urea peptides, and its screening for binding to the p56^lck SH2 domain. Several lead sequences were assessed for their relative binding affinity to the SH2 domain by competitive ELISA. The phosphotyrosine-urea peptides; A-urea-pYEELP, and D-urea-pYRTFG exhibited IC₅₀ values of 118nM and 285 nM respectively, compared to an IC₅₀ value of 34 nM obtained for the hmTpY324 sequence (EPQpYEEIPIYL, Kd = 1 nM to the p56^lck SH2 domain). The importance of the urea bond for binding was assessed by competitive ELISA, and its absence from the peptides resulted in a three-fold reduction in relative affinity. The bead binding assay was also utilised to screen several phosphatase-stable phosphonotyrosine analogues as replacements for phosphotyrosine in high affinity SH2 binding motifs. Results indicated that the mimetics; 4-[(phosphono)fluoromethyl]-phenylalanine, and 4-[(phosphono)hydroxymethyl]-phenylalaninate were suitable surrogates, with minimal reductions in the levels of binding exhibited. Combinatorial library strategies will prove invaluable in the discovery of new immunosuppressant and anticancer drugs. The solid phase N to C peptide synthesis methodology makes the C-terminus of peptides readily available for modification upon the solid support for the first time.