The site-directed alteration of genomic sequences by homologous replacement (1,2), psoralen mutation (3), or site-directed repair-mediated correction (4)is a technology that can be used to achieve a number of different ends, including:the introduction of specific mutations into vectors, development of transgenic animals, and gene therapy.Homologous replacement is versatile, in that sequences can be directly targeted and altered, inserted, or deleted.As such, it shows great potential for gene therapy to treat inherited genetic disorders for which the sequence information is known.Treatment involves direct conversion of mutant sequences to a wild-type genotype, thereby restoring the normal phenotype.Small-fragment homologous replacement (SFHR)is a technique that has shown promise in this application (5). SFHR has been used to correct the most common mutation associated with cystic fibrosis (CF), a 3-bp deletion in the CF transmembrane conductance regulator (CFTR)gene, resulting in the loss of a phenylalanine at amino acid position 508 (Δ508) (6–8).