Different combinatorial strategies have been employed to generate antibodies with novel specificities. On page 852, Söderlind et al. describe a new approach in which antibody framework regions are combined with sequences encoding in vivo-formed complementarity-determining regions (CDRs) of different germline origin (i.e., the hypervariable regions of the variable domains that interact with an antigen) and assembled by overlap extension using PCR. This approach yielded a human antibody single-chain fragment (scFv) library consisting of 2 × 109 members, which contained specific and strong binders to a variety of antigens. The approach, by varying up to as many as six in vivo-formed CDRs at a time, allows the creation of a high degree of functional variation in antibody molecules.