In Arabidopsis, the CLE genes encode a family of at least 32 peptide ligands. Our gain-of-function studies demonstrated that all of the 18 genes we examined caused pleiotropic and often opposing phenotypes, including various combinations of increased root and rosette growth, root stunting, dwarfing, shoot apical meristem (SAM) arrest, asymmetric leaf development, and "shrublike" phenotypes. Many CLE genes caused similar phenotypes that correlated with common amino acid substitutions among subsets of the genes, suggesting key amino acids necessary for certain phenotypes. The pleiotropic phenotypes we observed were the results of integrated hypermorphic and global neomorphic responses to abundant ectopic ligands through multiple signaling pathways. The phenotypes are also suggestive of wide ranging, often antagonistic roles played by these genes in plant development. The interpretations of our findings and some apparently contradictory recent results are discussed in this context.