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.