The solid-phase method introduced by Merrifield is now firmly established as a powerful technique for the study of bioligically important peptides, and indeed, it has been generalized to other biopolymers as well as many small organic compounds [combinatorial libraries]. Synthesis normally begins by covalently linking the starting (usually terminal) residue to an insoluble polymeric support. This anchoring step is an integral part of the overall synthetic plan, and the experimental details can impact significantly on the overall purity and yield of the final product. Handles are defined as bifunctional spacers, or linkers, which serve to achieve the required attachment in two discrete chemical steps. The handle approach allows precise control over the stability and ultimate cleavage of the anchoring linkage, and facilitates quantitative attachments which circumvent problems associated with extraneous polymer-bound functional groups. Under the aegis of the present research program, a number of handles [PAL, (R)PAL, HAL, XAL, BAL, NPE, Nonb, etc.] and polymeric supports [PEG-PS and CLEAR] have been developed and applied to the stepwise or segment condensation synthesis of challenging peptide targets. Some of these handle/support combinations are also appropriate for solid-phase organic synthesis. Compatible N alpha-amino [occasionally NW-amino] protection is provided principally by acid- labile tert-butyloxycarbonyl (Boc) or base-labile 9- fluorenylmethyloxycarbonyl (Fmoc) functions, and final cleavages occur under relatively mild conditions with minimal side reactions upon exposure to acid, base, light, fluoride ion, nucleophilic thiols, or palladium (0) in the presence of nucleophilic acceptors. Depending on the experimental design, the products can have a variety of endgroups (usually carboxylic acid or carboxamide), either completely free or else retaining side-chain protection. Some of the reagents and procedures developed in this research program have achieved widespread use throughout the world. The present competitive renewal application aims to expand on this progress and continue to demonstrate how the aforementioned handles can help address biologically significant challenges in synthetic peptide and combinatorial chemistry. Simultaneously, modified and new chemistries are being examined that may lead to new handles with even better properties and/or a wider range of uses. These methods will accommodate a range of scales, and be compatible with drug discovery programs and disease diagnosis procedures based on multiplex synthesis.