A new synthetic strategy for the preparation of highly branched, or dendritic-graft, polypeptides is presented. The synthetic strategy is based on a repetitive sequence of ring-opening copolymerization and deprotection steps. Comonomers for the ring-opening polymerization are a set of orthogonally protected L-lysine N-carboxyanhydride derivatives. After each polymerization step, selective removal of the is an element of-NH2 protecting groups of one of the monomers generates a number of new initiator sites that allow grafting of a successive generation of polypeptide branches. Following this strategy, dendritic-graft polypeptides containing up to similar to160 alpha-amino acids, corresponding to a number-average molecular weight of similar to40 kDa, could be obtained after only four ring-opening polymerization-deprotection cycles. In contrast to perfect dendrimers, the dendritic-graft polypeptides are neither structurally uniform nor monodisperse. Dendritic-graft polypeptides, however, are conveniently prepared in multigram quantities and do not require laborious purification procedures.