The therapeutic application of recombinant retroviruses and other integrating 
gene transfer vectors has been limited by problems of vector expression and 
vector-mediated genotoxicity. These problems arise in large part from the 
interactions between vector sequences and the genomic environment surrounding 
sites of integration. Strides have been made in overcoming both of these 
problems through the modification of deleterious vector sequences, the inclusion 
of better enhancers and promoters, and the use of alternative virus systems. 
However, these modifications often add other restrictions on vector design, 
which in turn can further limit therapeutic applications. As an alternative, 
several groups have been investigating a class of DNA regulatory elements known 
as chromatin insulators. These elements provide a means of blocking the 
interaction between an integrating vector and the target cell genome in a manner 
that is independent of the vector transgene, regulatory elements, or virus of 
origin. This review outlines the background, rationale, and evidence for using 
chromatin insulators to improve the expression and safety of gene transfer 
vectors. Also reviewed are topological factors that constrain the use of 
insulators in integrating gene transfer vectors, alternative sources of 
insulators, and the role of chromatin insulators as one of several components 
for optimal vector design.