Cyclic peptides offer the possibility of varying both scaffold geometry and R-group functionality. For example, parameters such as ring size and the placement of D-amino acid and proline residues can have a dramatic effect on the conformations of cyclic peptides, allowing access to structurally diverse species based on simple modifications in their linear sequences. We synthesized a cyclic peptide library in which ring size, alpha-carbon stereochemistry, and proline placement were varied. Analysis of the products showed that heptapeptides in general cyclized more readily than hexapeptides, and within these groups the scaffolds with a greater number of pralines cyclized with markedly lower yields than scaffolds with fewer pralines. Split-pool libraries based on a sample set of these scaffolds showed that, in general, scaffold geometry outweighed side chains variation in determining cyclization efficiency. These concepts were applied to the synthesis of cyclodimeric variants of an inhibitor of actin assembly in Xenopus egg extracts, yielding side chain variants with improved potency over the original scaffold.