Although biopolymers and synthetic polymers share many common features, each of these two classes of materials is also characterized by a distinct and very specific set of advantages and disadvantages. Combining biopolymer elements with synthetic polymers into a single macromolecular conjugate is an interesting strategy for synergetically merging the properties of the individual components and overcoming some of their limitations. This article focuses on a special class of biologi cal-synthetic hybrids that are obtained by site-selective conjugation of a protein or peptide and a synthetic polymer. The first part of the article gives an overview of the different liquid-phase and solid-phase techniques that have been developed for the synthesis of well-defined, that is, site-selectively conjugated, synthetic polymer-protein hybrids. In the second part, the properties and potential applications of these materials are discussed. The conjugation of biological and synthetic macromole cules allows the modulation of protein binding and recognition properties and is a powerful strategy for mediating the self-assembly of synthetic polymers. Synthetic polymer-protein hybrids are already used as medicines and show significant promise for bio-analytical applications and bio-separations. © 2004 Wiley Periodicals, Inc.