Cell shape has a dramatic influence on the organization of the cell and its genetic program. In the February 19 Proceedings of the National Academy of Sciences, Thomas et al. describe a method to investigate the link between nuclear shape and gene expression (Proc Natl Acad Sci USA 2002, 99:1972-1977). They studied primary osteogenic cells and measured changes in the expression of genes encoding differentiation markers, such as type I collagen and osteocalcin. They controlled cell shape using a microfabricated substrate with adhesive islands of defined shape and size, and combined this with sensitive reverse-transcription in situ PCR to measure changes in mRNA levels in individual cells. Thomas et al. could define optimal cell and nuclear shapes that resulted in maximal gene expression. This system will be useful in studies aiming to explore the connection between the cytoskeleton, the nuclear matrix and transcriptional regulation.